{"gene":"PIEZO1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2010,"finding":"Piezo1 (Fam38A) is an essential component of a mechanically activated (MA) cation channel. RNA interference knockdown of Piezo1 eliminated rapidly adapting MA currents in a mouse neuroblastoma cell line, and overexpression of mouse Piezo1 induced a kinetically distinct MA current, establishing Piezo1 as a pore-forming component of an MA cation channel.","method":"RNAi knockdown, overexpression, whole-cell and outside-out patch-clamp electrophysiology","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct electrophysiological reconstitution with gain- and loss-of-function in the same study; foundational paper replicated extensively","pmids":["20813920"],"is_preprint":false},{"year":2011,"finding":"The peptide GsMTx4 reversibly inhibits Piezo1-mediated mechanically activated currents in outside-out and whole-cell configurations, acting as a gating modifier (voltage-insensitive, active on closed channels) that shifts the pressure-gating curve ~30 mmHg rightward, with KD ~155 nM. The d-enantiomer was equally effective, consistent with membrane-mediated inhibition rather than stereospecific binding.","method":"Outside-out and whole-cell patch-clamp electrophysiology in HEK293 cells overexpressing Piezo1; kinetic rate-constant analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative electrophysiological characterization with pressure-gating curves, enantiomer controls, and rate-constant analysis in a single rigorous study","pmids":["21696149"],"is_preprint":false},{"year":2010,"finding":"Fam38A/Piezo1 localizes to the endoplasmic reticulum (ER) and activates integrin-ligand affinity by recruiting the small GTPase R-Ras to the ER, which increases Ca2+ release from cytoplasmic stores, activates calpain, and leads to talin cleavage. siRNA knockdown of Fam38A inactivates β1 integrin and reduces cell adhesion; this pathway is blocked by inhibition of R-Ras, calpain, or talin knockdown.","method":"siRNA knockdown, subcellular fractionation/immunofluorescence localization to ER, cell adhesion assays, pharmacological inhibition of R-Ras and calpain, co-immunoprecipitation","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (localization, knockdown, pharmacological inhibition, epistasis) in a single lab; ER localization finding is distinct from later plasma-membrane mechanosensing studies","pmids":["20016066"],"is_preprint":false},{"year":2012,"finding":"Gain-of-function mutations in PIEZO1 (FAM38A) cause hereditary xerocytosis (HX), an autosomal dominant hemolytic anemia with primary erythrocyte dehydration. PIEZO1 peptides were identified by discovery proteomics in human erythrocyte membranes, establishing Piezo1 as an endogenous erythrocyte membrane protein.","method":"Copy number analysis, linkage studies, exome sequencing, segregation analysis, discovery proteomics of erythrocyte membranes","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — human genetics with segregation in two kindreds, proteomics confirmation of protein in erythrocyte membrane; independently replicated by subsequent studies","pmids":["22529292"],"is_preprint":false},{"year":2014,"finding":"Piezo1 is expressed in endothelial cells of developing blood vessels and is activated by shear stress. Endothelial-specific Piezo1 deletion is embryonic lethal with vascular remodeling defects, and loss of Piezo1 impairs shear-stress-induced stress fiber formation and cell orientation, linking Piezo1 mechanotransduction to regulation of endothelial cell morphology.","method":"Conditional endothelial-specific knockout mice, shear stress application, cell orientation and stress fiber assays, in vivo vascular phenotyping","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — endothelial-specific genetic deletion with defined embryonic lethal vascular phenotype, shear stress activation confirmed, cellular morphology readout; replicated by multiple subsequent labs","pmids":["24958852"],"is_preprint":false},{"year":2015,"finding":"Yoda1, a synthetic small molecule identified by screening ~3.25 million compounds, acts as a chemical agonist for both human and mouse Piezo1, affecting sensitivity and inactivation kinetics of mechanically induced responses. Yoda1 activates purified Piezo1 channels reconstituted in artificial droplet lipid bilayers in the absence of other cellular components, demonstrating direct channel activation.","method":"Cell-based fluorescence screening, electrophysiology, reconstitution of purified Piezo1 in droplet lipid bilayers","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct reconstitution of purified channel in lipid bilayers with small-molecule agonist; independently used as tool compound by dozens of subsequent labs","pmids":["26001275"],"is_preprint":false},{"year":2015,"finding":"Red blood cells exhibit Piezo1-dependent calcium entry in response to mechanical stretch. RBC-specific Piezo1 conditional knockout produces overhydrated, fragile RBCs. Piezo1 activation by Yoda1 causes calcium influx and subsequent RBC dehydration via downstream activation of the KCa3.1 Gardos channel, establishing the Piezo1→Gardos channel axis for RBC volume control.","method":"RBC-specific conditional knockout mice, calcium imaging, RBC fragility assays (in vitro and in vivo), Yoda1 pharmacology, Gardos channel pharmacological dissection","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with cellular phenotype, pharmacological dissection of downstream pathway, multiple orthogonal methods; replicated by subsequent hereditary xerocytosis studies","pmids":["26001274"],"is_preprint":false},{"year":2017,"finding":"Mechanical stretch stimulates epithelial cell division through Piezo1. Stretch triggers cells paused in early G2 to activate calcium-dependent phosphorylation of ERK1/2, activating cyclin B transcription to drive mitosis. Piezo1 subcellular localization differs with cell density: in sparse (dividing) regions it localizes to the plasma membrane and cytoplasm, while in dense (extruding) regions it forms large cytoplasmic aggregates.","method":"Mechanical stretch of epithelia, calcium imaging, phospho-ERK assays, cyclin B reporter assays, Piezo1 knockdown, live-cell imaging of Piezo1 localization","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (stretch, knockdown, signaling assays, live localization imaging) in a single rigorous study establishing mechanism","pmids":["28199303"],"is_preprint":false},{"year":2019,"finding":"Dietary fatty acids tune Piezo1 mechanical response: margaric acid (a saturated fatty acid) inhibits Piezo1 activation by increasing membrane bending stiffness, whereas polyunsaturated fatty acids (PUFAs) modulate channel inactivation by decreasing membrane bending stiffness. Fatty acid supplementation can abrogate gain-of-function Piezo1 mutation phenotypes.","method":"Lipid profiling, electrophysiology, atomic force microscopy membrane stiffness measurements, fatty acid supplementation in gain-of-function Piezo1 mutant cells","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — electrophysiology combined with direct membrane stiffness measurements and functional rescue of disease mutation phenotypes; multiple orthogonal methods in one study","pmids":["30867417"],"is_preprint":false},{"year":2019,"finding":"Piezo1 is required for bone formation by osteoblasts: knockout of Piezo1 in osteoblast lineage cells disrupts osteogenesis and impairs bone structure and strength, and simulated microgravity suppresses Piezo1 expression in osteoblasts to reduce their function.","method":"Osteoblast-lineage-specific conditional knockout mice, bone histology and biomechanical testing, microgravity simulation, gene expression analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional cell-type-specific knockout with defined bone phenotype; replicated by independent group (PMID 31588901)","pmids":["31290742"],"is_preprint":false},{"year":2019,"finding":"Piezo1 mediates fluid shear stress-induced gene expression changes in osteocytes, and conditional deletion of Piezo1 in osteoblasts and osteocytes reduces bone mass and strength. Administration of a Piezo1 agonist (Yoda1) to adult mice increases bone mass, mimicking mechanical loading.","method":"Fluid shear stress assays in cultured osteocytes, conditional knockout mice, in vivo Yoda1 administration, bone mass and strength measurements","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic deletion plus pharmacological gain-of-function in vivo; replicates and extends PMID 31290742","pmids":["31588901"],"is_preprint":false},{"year":2019,"finding":"Piezo1 activation leads to ATP release from cells, which acts as an autocrine/paracrine signal activating P2 purinergic receptors to regulate cell functions. Piezo1-mediated mechanotransduction thus couples mechanical stimulation to downstream purinergic signaling.","method":"ATP release assays, P2 receptor pharmacology, Piezo1 knockdown/activation experiments across multiple cell types","journal":"Frontiers in Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — review synthesizing multiple experimental findings from multiple labs, but original experimental evidence cited is indirect; single mechanistic claim supported by referenced primary studies","pmids":["31780935"],"is_preprint":false},{"year":2020,"finding":"Piezo1 in mature adipocytes mediates diet-induced adipogenesis by releasing adipogenic fibroblast growth factor 1 (FGF1) upon channel opening, which induces adipocyte precursor differentiation through activation of FGF receptor 1. Mice lacking Piezo1 in mature adipocytes show defective preadipocyte differentiation on high-fat diet.","method":"Mature adipocyte-specific conditional Piezo1 knockout mice, high-fat diet challenge, FGF1 measurement, FGFR1 pharmacological inhibition, adipogenesis assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with dietary challenge, ligand identification (FGF1), receptor pharmacological dissection; multiple orthogonal methods","pmids":["32385276"],"is_preprint":false},{"year":2020,"finding":"Gut Piezo1 in enterochromaffin cells functions as a sensor for single-stranded RNA (ssRNA) from fecal microbiota, governing serotonin (5-HT) production. Intestinal epithelium-specific Piezo1 deletion profoundly disturbs gut peristalsis and suppresses serum 5-HT levels. Colonic infusion of RNase A suppressed gut motility and increased bone mass, confirming the ssRNA–Piezo1 axis.","method":"Intestinal epithelium-specific conditional Piezo1 knockout, fecal ssRNA identification as ligand, RNase A infusion experiments, calcium imaging, bone mass measurement","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined phenotype, identification of ssRNA as natural ligand, orthogonal RNase A experiment, multiple readouts","pmids":["32640190"],"is_preprint":false},{"year":2021,"finding":"Piezo1 is a key regulator of macrophage phagocytic activity and erythrocyte turnover, controlling hepcidin levels and iron metabolism. Constitutive or macrophage-specific expression of a gain-of-function Piezo1 allele in mice causes iron overload, and the E756del allele (present in ~1/3 of individuals of African descent) is strongly associated with increased plasma iron.","method":"Constitutive and macrophage-specific conditional knock-in of GOF Piezo1 allele in mice, hepcidin measurement, erythrocyte turnover assays, human genetic association in African Americans","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional macrophage-specific GOF allele in mice with defined hepcidin and iron phenotype, human genetic validation; multiple orthogonal approaches","pmids":["33571427"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM of PIEZO1 reconstituted in liposome vesicles revealed curved (resting) and flattened (activated) structural states. Membrane tension induces flattening of the blade (~300 nm2 in-plane area expansion), bending of the beam, and detaching/rotating of the cap, collectively gating the ion-conducting pathway. The calculated half-maximal activation tension (~1.9 pN/nm) matches experimental values.","method":"Cryo-EM structural determination of Piezo1 in liposomes, in-plane area and stiffness calculations, comparison with detergent-solubilized structures","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures in lipid bilayer with functional validation via matching calculated and experimental gating tensions; rigorous structural study","pmids":["35388220"],"is_preprint":false},{"year":2022,"finding":"Lipid peroxidation during ferroptosis increases plasma membrane tension, activating Piezo1 and TRP channels, causing cation permeability (Na+/Ca2+ influx, K+ efflux). Piezo1 deletion reduces these cation permeability changes. Oxidized lipids also depress Na+/K+-ATPase activity, and preventing cation content changes attenuates ferroptosis.","method":"Piezo1 deletion, calcium/sodium/potassium flux measurements, ruthenium red/2-APB channel blockers, ferroptosis induction (GPX4 inhibition), membrane tension measurement","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion of Piezo1 with pharmacological confirmation, direct membrane tension measurements, multiple ion flux readouts establishing mechanism","pmids":["36898371"],"is_preprint":false},{"year":2022,"finding":"Astrocytic Piezo1 mediates mechanically evoked Ca2+ responses and ATP release (mechano-chemo transduction). Piezo1 deletion in astrocytes severely impairs adult hippocampal neurogenesis and abolishes ATP-dependent potentiation of neural stem cell proliferation. Overexpression of Piezo1 in astrocytes enhances LTP and learning/memory performance.","method":"Astrocyte-specific conditional knockout, in vivo neurogenesis assays, hippocampal LTP recordings, behavioral tests, ATP release measurement, Piezo1 overexpression","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation (knockout and overexpression) with multiple orthogonal mechanistic readouts (Ca2+, ATP, neurogenesis, LTP, behavior)","pmids":["35963237"],"is_preprint":false},{"year":2022,"finding":"PECAM1 interacts with PIEZO1 and directs it to endothelial cell-cell junctions. PECAM1 extracellular N-terminus is critical for this interaction; CDH5 also drives PIEZO1 to junctions but its interaction is dynamic and increases with shear stress. PIEZO1 does not interact with VEGFR2. PIEZO1 is required for Ca2+-dependent formation of adherens junctions and associated cytoskeleton.","method":"Non-disruptive tagging of native PIEZO1 in mice, reconstitution experiments, high-resolution co-localization microscopy, co-immunoprecipitation, shear stress experiments, adherens junction assays","journal":"Communications Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — native-tagged protein in mice, reconstitution, reciprocal Co-IP, high-resolution microscopy; multiple orthogonal methods in one study","pmids":["37005489"],"is_preprint":false},{"year":2022,"finding":"Endothelial PIEZO1 mediates leukocyte diapedesis: leukocyte-induced clustering of ICAM-1 synergizes with fluid shear stress to increase endothelial membrane tension and activate PIEZO1, elevating [Ca2+]i and driving phosphorylation of SRC, PYK2, and myosin light chain, opening the endothelial barrier. Endothelium-specific Piezo1 deficiency reduces leukocyte extravasation in vivo.","method":"Endothelial-specific conditional knockout mice, Ca2+ imaging, phospho-SRC/PYK2/MLC measurements, in vivo inflammation models, ICAM-1 clustering assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional endothelial knockout with in vivo phenotype, defined signaling cascade with multiple phosphorylation readouts, mechanistic dissection of ICAM-1/shear stress synergy","pmids":["35443048"],"is_preprint":false},{"year":2022,"finding":"Piezo1 activation by matrix stiffness in macrophages promotes M1 polarization via the YAP signaling axis. Increased matrix stiffness upregulates Piezo1 expression and activates YAP, favoring M1 and suppressing M2 polarization. YAP inhibitor treatment re-polarizes macrophages to M2.","method":"Polyacrylamide gels of varying stiffness, Piezo1 expression analysis, YAP activation assays, pharmacological YAP inhibition, macrophage polarization markers, in vivo implant model","journal":"Cell Proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, defined substrate stiffness system with YAP pathway dissection, but signaling link between Piezo1 and YAP not fully mechanistically resolved","pmids":["38556840"],"is_preprint":false},{"year":2022,"finding":"Piezo1 activation in renal proximal tubular cells by mechanical stretch, compression, or matrix stiffness causes calcium influx, activates calpain2, cleaves talin1, and upregulates integrin β1, driving profibrotic responses. TGF-β1 also upregulates Piezo1 expression to drive profibrotic changes via this pathway.","method":"HK2 cells and primary mouse proximal tubular cells under mechanical stimulation, Yoda1 pharmacology, Piezo1 siRNA/inhibitor, calpain2 activity assay, talin1 cleavage by western blot, integrin β1 assay, UUO/folic acid mouse models with GsMTx4 treatment","journal":"JCI Insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro mechanistic dissection with multiple pathway components (calcium/calpain2/talin1/integrin β1) combined with in vivo mouse fibrosis models and pharmacological intervention","pmids":["35230979"],"is_preprint":false},{"year":2022,"finding":"Piezo1 activation promotes Yap/Taz nuclear localization in periosteal stem cells, which in turn increases β-catenin nuclear localization. YAP directly interacts with β-catenin in the nucleus forming a transcriptional YAP/β-catenin complex that upregulates osteogenic, chondrogenic, and angiogenic factors including VEGF-A.","method":"Piezo1 agonist Yoda1 treatment of periosteal stem cells, YAP nuclear localization imaging, co-immunoprecipitation of YAP and β-catenin, gene expression assays, conditional knockout mice, fracture healing mouse model","journal":"International Journal of Biological Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of YAP/β-catenin, nuclear localization imaging, genetic and pharmacological manipulation; single lab but multiple orthogonal methods","pmids":["35844802"],"is_preprint":false},{"year":2023,"finding":"Direct nanoscopic fluorescence imaging of PIEZO1 in living cells revealed that blades are significantly expanded at rest by plasma membrane bending stress, more so than predicted from detergent-solubilized structures. Blade expansion correlates with channel activation, and blade flexibility varies along its length due to decreased inter-subdomain binding strength.","method":"Single-molecule nanoscopic fluorescence imaging (dSTORM/PAINT) of endogenously tagged PIEZO1 in live cells, chemical and mechanical modulators of channel activity","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Moderate — novel single-molecule structural approach in native cellular context with functional correlations; rigorous study with multiple modulators","pmids":["37587339"],"is_preprint":false},{"year":2023,"finding":"Piezo1 provides the mechanistic link between mechanical signals and EGFR-ERK activation. Piezo1 activation triggers clathrin-mediated EGFR endocytosis and ERK activation via Src-p38 kinase-dependent serine phosphorylation of EGFR (not canonical EGF-induced tyrosine autophosphorylation). This Piezo1-dependent pathway promotes nuclear ERK, AP-1 (FOS/JUN), and YAP accumulation.","method":"Piezo1 agonist/antagonist pharmacology, EGFR endocytosis assays, phosphorylation site analysis (serine vs tyrosine), Src and p38 inhibitors, nuclear ERK/AP-1/YAP imaging, ex vivo lung slice experiments","journal":"Science Advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (endocytosis assays, phospho-site analysis, kinase inhibitors), single lab; mechanistic distinction from canonical EGF pathway well supported","pmids":["37756411"],"is_preprint":false},{"year":2023,"finding":"Membrane stretch (detected by AFM with FEM modeling) is the mechanism of PIEZO1 gating in chondrocytes. PIEZO1 drives Ca2+ signaling independently at the highest strains, and factors increasing apparent membrane tension (hypoosmotic prestrain, high compression, low deformation rates) increase PIEZO1-driven Ca2+ signaling. The threshold membrane stretch ratio for PIEZO1 activation is λ=1.9.","method":"Single-cell AFM compression, finite element modeling, calcium imaging, PIEZO1/2 knockout chondrocytes, hypoosmotic treatment, pharmacological channel blockers","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — AFM+FEM biophysical characterization with genetic knockout, defines quantitative biophysical gating threshold; rigorous multi-method study","pmids":["37459546"],"is_preprint":false},{"year":2023,"finding":"PIEZO1 activation in lymphatic endothelial cells by fluid flow causes rapid exocytosis of ANGPT2, ectodomain shedding of TIE1 by ADAM17, and increased TIE/PI3K/AKT signaling, followed by nuclear export of the transcription factor FOXO1, establishing a functional molecular network linking PIEZO1 mechanosensing to transcriptional regulation in lymphatic vessels.","method":"Piezo1 activation/inhibition in cultured LECs, ANGPT2 exocytosis assays, TIE1 shedding assays (ADAM17 involvement), PI3K/AKT/FOXO1 signaling analysis, conditional knockout mice","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined multi-step signaling cascade (PIEZO1→ANGPT2 exocytosis→ADAM17/TIE1 shedding→PI3K/AKT→FOXO1) with genetic and pharmacological dissection","pmids":["38747287"],"is_preprint":false},{"year":2023,"finding":"Piezo1 activation in neutrophils during trans-endothelial migration generates spike-like Ca2+ signals, upregulates NADPH oxidase 4 (NOX4), and enhances bactericidal function. PMN-specific Piezo1 deletion impairs bacterial clearance in vivo. Mechanical forces in microfluidic systems recapitulate Piezo1-dependent NOX4 upregulation and bactericidal activation.","method":"Piezo1-specific conditional knockout in PMNs, intravital imaging, calcium imaging, microfluidic systems, NOX4 expression assays, in vivo bacterial infection models, adoptive transfer experiments","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic knockout, microfluidic mechanical recapitulation, in vivo infection model, adoptive transfer; multiple orthogonal methods across two platforms","pmids":["38091995"],"is_preprint":false},{"year":2023,"finding":"Piezo1 channels in brain capillary endothelial cells function as mechanosensors: activation by mechanical forces evokes Ca2+ signals in capillary endothelial cells, and these currents are absent upon endothelial cell-specific Piezo1 deletion.","method":"Electrophysiology of brain cortical and retinal capillaries, endothelial-specific Piezo1 deletion, genetically encoded Ca2+ indicator mice, ex vivo pressurized retina preparation","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — electrophysiological confirmation in native capillaries, genetic deletion specificity control, live Ca2+ imaging in pressurized retina preparation","pmids":["35382561"],"is_preprint":false},{"year":2023,"finding":"Piezo1 activation increases intracellular Ca2+ in shear-stressed neutrophils, mediating calpain activity and cytoskeleton remodeling, which consequently induces NETosis. Shear-stress-induced NETosis is dependent on Piezo1 expression and is enhanced by NETosis-inducing agents.","method":"Microfluidics shear stress application, Piezo1 knockdown/overexpression, calcium imaging, calpain activity assays, cytoskeleton imaging, NET quantification","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (microfluidics, calcium, calpain, cytoskeleton), single lab, defined mechanistic pathway","pmids":["39174529"],"is_preprint":false},{"year":2023,"finding":"Piezo1 in gastric X/A-like cells senses gastric distention and inhibits ghrelin production through the CaMKKII/CaMKIV-mTOR signaling pathway. X/A-like cell-specific Piezo1 knockout causes hyperghrelinemia, hyperphagia, and susceptibility to overweight; Piezo1 activation by Yoda1 or gastric bead implantation inhibits ghrelin production and decreases food intake.","method":"X/A-like cell-specific conditional Piezo1 knockout, Yoda1 pharmacology, gastric bead implantation, ghrelin measurements, CaMKKII/CaMKIV/mTOR pathway analysis in mHypoE-42 cell line","journal":"Nature Metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockout with in vivo metabolic phenotypes, orthogonal mechanical activation (bead implantation), defined signaling cascade in relevant cell line","pmids":["38467889"],"is_preprint":false},{"year":2024,"finding":"PIEZO1 activation in red blood cells triggers Ca2+ influx through PIEZO1, which activates TMEM16F (the long-sought-after RBC phosphatidylserine scramblase). PIEZO1-TMEM16F functional coupling is enhanced in hereditary xerocytosis RBCs with PIEZO1 gain-of-function mutations, leading to increased PS exposure. GsMTx-4 and benzbromarone inhibit PIEZO1 and prevent force-induced PS exposure and hemolysis.","method":"Calcium influx assays, PS exposure assays, TMEM16F functional coupling in normal and HX patient RBCs, pharmacological inhibition with GsMTx-4 and benzbromarone, echinocytosis/hemolysis assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional coupling between PIEZO1 and TMEM16F established in human disease RBCs with pharmacological dissection; multiple mechanistic readouts","pmids":["38033286"],"is_preprint":false},{"year":2024,"finding":"PIEZO1 in cytotoxic T cells upregulates the transcription factor GRHL3, which induces expression of the E3 ubiquitin ligase RNF114. RNF114 binds to filamentous actin causing its downregulation and rearrangement, depressing traction forces in T cells. Blocking PIEZO1 strengthens traction forces and augments cytotoxicity against tumor cells.","method":"PIEZO1 knockout/antagonist treatment of cytotoxic T cells, traction force microscopy, GRHL3/RNF114 expression analysis, F-actin imaging, tumor killing assays, in vivo tumor model with adoptive T cell transfer","journal":"Nature Biomedical Engineering","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined PIEZO1→GRHL3→RNF114→F-actin→traction force pathway with multiple orthogonal methods, in vivo validation","pmids":["38514773"],"is_preprint":false},{"year":2024,"finding":"Macrophage Piezo1 promotes progression of liver fibrosis by activating the Ca2+-dependent calpain protease, which drives CTSS (cathepsin S) secretion via cleavage of lysosome-associated membrane protein-1 (LAMP1). Myeloid-specific Piezo1 knockout reduces macrophage inflammation, CTSS secretion, and liver fibrosis.","method":"Myeloid-specific conditional Piezo1 knockout mice, RNA-seq, CTSS activity assays, calpain inhibition, LAMP1 cleavage western blot, liver fibrosis models (CCl4/BDL)","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with RNA-seq pathway identification, mechanistic LAMP1 cleavage assay, pharmacological calpain inhibition; single lab","pmids":["37908726"],"is_preprint":false},{"year":2024,"finding":"Piezo1 in ILC2s restrains group 2 innate lymphoid cell-driven type 2 lung inflammation. Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner by reducing ILC2 oxidative metabolism. Genetic ablation of Piezo1 in ILC2s exacerbates airway hyperreactivity.","method":"ILC2-specific conditional Piezo1 knockout mice, Yoda1 pharmacology, cytokine secretion assays, proliferation assays, KLF2 knockdown, metabolic assays (oxidative phosphorylation), in vivo AHR models, humanized mouse models","journal":"Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional cell-type-specific knockout, pharmacological activation, KLF2-dependency established, human ILC2 validation, multiple orthogonal methods","pmids":["38530239"],"is_preprint":false},{"year":2024,"finding":"Disturbed flow activates Piezo1 in endothelial cells, causing Ca2+ influx that activates the CaM/CaMKII pathway, which phosphorylates FAK and Src, activating YAP and triggering endothelial inflammation. GsMTx4 inhibition of Piezo1 delays atherosclerotic plaque progression.","method":"Oscillatory shear stress application, Ca2+ imaging, pharmacological inhibition (GsMTx4, CaMKII inhibitor), FAK/Src/YAP phosphorylation assays, ApoE-/- atherosclerosis mouse model","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined Ca2+/CaM/CaMKII/FAK/Src/YAP cascade with pharmacological dissection and in vivo plaque model; single lab","pmids":["39450718"],"is_preprint":false},{"year":2024,"finding":"Macrophage Piezo1 activation promotes efferocytosis on rigid substrates and facilitates efficient acidification of engulfed cargo in phagolysosomes, driving anti-inflammatory gene expression after efferocytosis. Macrophage-specific Piezo1 knockout impairs efferocytosis and spontaneous resolution of early liver fibrosis.","method":"Macrophage-specific conditional Piezo1 knockout, polyacrylamide gel stiffness assays, phagolysosomal acidification assays, anti-inflammatory gene expression, in vivo liver fibrosis resolution model, Yoda1 pharmacology","journal":"Science Advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with in vivo phenotype, phagolysosomal functional assay, stiffness-dependent efferocytosis established; single lab","pmids":["38838160"],"is_preprint":false},{"year":2024,"finding":"Piezo1 in podocytes triggers a signaling loop involving NFATc1 and TRPC6, leading to increased calcium influx and perpetuating podocyte injury in diabetic kidney disease. TRPC6 overexpression in podocyte-specific Piezo1 knockout mice counteracted the protective effects of Piezo1 deletion, confirming the Piezo1/NFATc1/TRPC6 axis.","method":"Podocyte-specific Piezo1 conditional knockout mice, DKD model (STZ+HFD), in vitro calcium influx assays, NFATc1 and TRPC6 expression analysis, AAV-mediated TRPC6 overexpression rescue experiment","journal":"JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with rescue experiment (TRPC6 overexpression), in vivo DKD model, defined NFATc1/TRPC6 downstream pathway; single lab","pmids":["39932793"],"is_preprint":false},{"year":2025,"finding":"Piezo1 in pulmonary myofibroblasts (periostin+ cells) mediates mechanosensation essential for myofibroblast activation and lung fibrosis. Loss of Piezo1 in periostin+ cells disrupts actin organization and prevents Yap/Taz nuclear localization, shifting myofibroblasts from a proliferative to an apoptotic state. Myofibroblast-specific Yap/Taz deletion fully recapitulates protective Piezo1-KO phenotypes.","method":"Postn-specific conditional Piezo1 knockout mice, actin organization imaging, Yap/Taz nuclear localization assays, myofibroblast-specific Yap/Taz knockout for epistasis, bleomycin pulmonary fibrosis model","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout in specific cell type, epistasis experiment (Yap/Taz KO recapitulates Piezo1 KO), defined actin→Yap/Taz nuclear pathway, in vivo disease model","pmids":["40454481"],"is_preprint":false},{"year":2025,"finding":"PIEZO1 in vascular smooth muscle cells attenuates Marfan syndrome aortic aneurysm by inhibiting the TGF-β signaling pathway through promoting endocytosis and autophagy of TGF-β receptor 2 (TGFBR2) via Rab GTPase 3C. Smooth muscle cell-specific Piezo1 knockout exacerbates aneurysm and TGF-β pathway activation; Yoda1 activation reverses aneurysm development.","method":"VSMC-specific conditional Piezo1 knockout in MFS mice, TGFBR2 endocytosis and autophagy assays, Rab3C involvement, Yoda1 pharmacological treatment in vivo, TGF-β pathway signaling assays","journal":"European Heart Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional VSMC-specific knockout with in vivo aortic phenotype, TGFBR2 endocytosis/autophagy mechanistic dissection via Rab3C; single lab","pmids":["39585648"],"is_preprint":false},{"year":2025,"finding":"Piezo1 in cardiomyocytes is elevated in diabetic cardiomyopathy and promotes mitochondrial fission via calpain activation and Drp1 dephosphorylation. Cardiac-specific Piezo1 knockout restores ERK1/2-mediated Drp1 phosphorylation (inhibitory), preserves mitochondrial dynamics, and ameliorates diabetic cardiac dysfunction and fibrosis.","method":"Cardiac-specific conditional Piezo1 knockout mice (STZ and HFD+STZ models), echocardiography, calpain activity assays, Drp1/ERK phosphorylation western blots, mitochondrial morphology and respiration assays, H9C2 cells and neonatal cardiomyocytes","journal":"Cardiovascular Diabetology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with in vivo cardiac phenotype, defined calpain/Drp1/ERK mechanistic pathway, multiple mitochondrial readouts; single lab","pmids":["40114130"],"is_preprint":false},{"year":2022,"finding":"Piezo1 activation stimulates mitochondrial calcium uptake and oxidative phosphorylation (OXPHOS). Loss of Piezo1 reduces mitochondrial oxygen consumption rate and ATP production in calvarial cells, associated with increased phosphodiesterase Pde4a expression and lower cAMP levels. cAMP signaling via PKA is required for the Piezo1-induced increase in mitochondrial OXPHOS.","method":"Piezo1 conditional knockout and agonist treatment in calvarial cells, Seahorse OCR measurements, cAMP reporter assays, phosphodiesterase inhibition, PKA inhibition, mitochondrial calcium imaging","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway components tested (cAMP, PKA, phosphodiesterase), defined signaling mechanism, Seahorse metabolic measurements; single lab","pmids":["36052712"],"is_preprint":false},{"year":2022,"finding":"Piezo1 in lymphatic endothelial cells acts as the upstream mechanosensor for flow-induced Orai1-KLF2-Notch lymphatic mechanotransduction pathway. Piezo1 knockdown blocks laminar flow-induced calcium influx and Orai1 downstream gene regulation; Piezo1 stimulation activates Orai1 signaling without fluid flow; Orai1 inhibition blocks Piezo1-mediated mechanotransduction, establishing Piezo1 epistatic to Orai1.","method":"Lymphatic endothelial cell Piezo1 knockdown, flow-induced calcium imaging, lymphatic-specific conditional Piezo1 knockout mice, Orai1 inhibition for epistasis, in vivo lymphatic regeneration model, Yoda1 pharmacology for lymphedema treatment","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — formal epistasis (Orai1 inhibition blocks Piezo1 effect), conditional knockout phenocopies downstream pathway knockouts, in vivo therapeutic validation; multiple orthogonal methods","pmids":["35701867"],"is_preprint":false}],"current_model":"PIEZO1 is a large homotrimeric mechanosensitive cation channel that senses membrane tension, curvature, and mechanical deformation through its curved blade-beam-pore architecture, undergoing tension-driven flattening (~300 nm² area expansion) to gate a calcium-permeable conductance; downstream calcium influx activates cell-type-specific cascades including the Gardos channel (erythrocyte volume), KCa3.1/TMEM16F (RBC PS exposure), calpain/talin/integrin β1 (adhesion and fibrosis), ERK/cyclin B (cell division), Src-p38-EGFR (regenerative signaling), cAMP/PKA (mitochondrial OXPHOS), CaMKII/YAP (mechanotransduction in bone, cartilage, and vascular cells), NFATc1/TRPC6 (podocyte injury), GRHL3/RNF114/F-actin (T cell cytotoxicity), and ATP-P2 purinergic paracrine signaling, while its gating is modulated by lipid composition (fatty acids, cholesterol), the agonist Yoda1, and the gating-modifier peptide GsMTx4, and its activity is regulated by direct protein interactions with PECAM1 and CDH5 at endothelial junctions."},"narrative":{"mechanistic_narrative":"PIEZO1 is a pore-forming, mechanically activated, calcium-permeable cation channel that transduces membrane tension and mechanical deformation into cellular calcium signals across diverse tissues [PMID:20813920]. Its gating is intrinsic to the protein and to its lipid environment: cryo-EM in liposomes shows the channel adopts a curved resting state that flattens (~300 nm² in-plane area expansion) under membrane tension to open the conduction pathway, with a calculated half-maximal gating tension (~1.9 pN/nm) matching experiment [PMID:35388220], and single-molecule imaging in live cells confirms that the blades are bent by resting membrane stress and expand upon activation [PMID:37587339]. Membrane mechanics tune sensitivity directly — saturating versus polyunsaturated fatty acids modulate activation and inactivation by altering bilayer bending stiffness [PMID:30867417] — while the synthetic agonist Yoda1 activates purified channels reconstituted in lipid bilayers and the peptide GsMTx4 inhibits gating as a membrane-mediated modifier [PMID:26001275, PMID:21696149]. At the cellular level, PIEZO1 couples mechanical input to calcium-dependent effectors that are interpreted in a cell-type-specific manner: in erythrocytes stretch-driven calcium influx engages the KCa3.1 Gardos channel to control cell volume and TMEM16F to drive phosphatidylserine exposure [PMID:26001274, PMID:38033286]; in fibroblasts, tubular, and myeloid cells calcium activates calpain-mediated talin cleavage, integrin β1, and YAP/TAZ signaling to drive adhesion, fibrosis, and macrophage polarization [PMID:35230979, PMID:40454481, PMID:38556840]; and in endothelial and lymphatic cells shear stress activates PIEZO1 to control junction formation, leukocyte diapedesis, and the Orai1–KLF2–Notch and ANGPT2/TIE1 mechanotransduction networks [PMID:37005489, PMID:35443048, PMID:35701867, PMID:38747287]. PIEZO1 also acts as a chemo-mechanosensor — sensing microbial single-stranded RNA in gut enterochromaffin cells to govern serotonin output [PMID:32640190] — and broadly couples mechanical stimulation to paracrine release of ATP, FGF1, and other ligands [PMID:31780935, PMID:32385276, PMID:35963237]. Gain-of-function mutations in PIEZO1 cause hereditary xerocytosis, a dominant hemolytic anemia with erythrocyte dehydration [PMID:22529292].","teleology":[{"year":2010,"claim":"Established the molecular identity of a long-sought mechanically activated cation channel, answering whether a single gene product could constitute a mechanosensor.","evidence":"RNAi knockdown and overexpression with patch-clamp electrophysiology in neuroblastoma and HEK293 cells","pmids":["20813920"],"confidence":"High","gaps":["Did not resolve the channel's oligomeric state or structural basis of gating","Endogenous physiological force inputs not defined"]},{"year":2010,"claim":"Proposed an early intracellular role linking Fam38A/Piezo1 to integrin activation via an ER-localized R-Ras/calpain/talin cascade, distinct from later plasma-membrane mechanosensing.","evidence":"siRNA knockdown, subcellular fractionation, co-IP, and pharmacological epistasis in adherent cells","pmids":["20016066"],"confidence":"Medium","gaps":["ER localization is hard to reconcile with later plasma-membrane channel function","Whether calcium release was from ER stores versus extracellular influx not definitively resolved"]},{"year":2011,"claim":"Characterized GsMTx4 as a membrane-mediated gating modifier, providing a pharmacological tool and evidence that gating is sensitive to bilayer mechanics rather than a stereospecific binding pocket.","evidence":"Patch-clamp with pressure-gating curves, enantiomer controls, and kinetic analysis in Piezo1-expressing HEK293 cells","pmids":["21696149"],"confidence":"High","gaps":["Molecular site of action on the channel/membrane not mapped","Selectivity versus other mechanosensitive channels limited"]},{"year":2012,"claim":"Linked PIEZO1 to human disease, showing gain-of-function mutations cause hereditary xerocytosis and confirming PIEZO1 is an endogenous erythrocyte membrane protein.","evidence":"Linkage, exome sequencing, segregation in kindreds, and erythrocyte membrane proteomics","pmids":["22529292"],"confidence":"High","gaps":["Did not establish the downstream effector linking channel hyperactivity to dehydration","Mutation effects on gating biophysics not yet measured"]},{"year":2014,"claim":"Defined PIEZO1 as the endothelial shear-stress sensor required for vascular development and flow-induced cytoskeletal remodeling.","evidence":"Endothelial-specific conditional knockout mice with shear stress, cell orientation, and stress fiber assays","pmids":["24958852"],"confidence":"High","gaps":["Downstream signaling from calcium influx to cytoskeletal reorganization not detailed","Embryonic lethality limited adult vascular analysis"]},{"year":2015,"claim":"Provided a synthetic agonist (Yoda1) acting directly on purified channels and resolved the erythrocyte volume-control pathway downstream of PIEZO1.","evidence":"Compound screening with bilayer reconstitution of purified Piezo1; RBC-specific knockout with calcium imaging and Gardos channel pharmacology","pmids":["26001275","26001274"],"confidence":"High","gaps":["Yoda1 binding site and activation mechanism not structurally defined in 2015","Direct coupling between PIEZO1 calcium and Gardos channel not molecularly mapped"]},{"year":2017,"claim":"Connected mechanical stretch to cell-cycle progression, showing PIEZO1 drives calcium-ERK-cyclin B signaling and changes localization with cell density.","evidence":"Epithelial stretch, calcium imaging, phospho-ERK and cyclin B assays, knockdown, and live-cell PIEZO1 imaging","pmids":["28199303"],"confidence":"High","gaps":["Mechanism of density-dependent cytoplasmic aggregation unresolved","Link between calcium and ERK activation not molecularly defined"]},{"year":2019,"claim":"Established PIEZO1 as a tunable sensor whose set-point is controlled by membrane lipid composition, with therapeutic implications for gain-of-function disease.","evidence":"Lipid profiling, electrophysiology, AFM membrane stiffness measurement, and fatty acid rescue of GOF mutant phenotypes","pmids":["30867417"],"confidence":"High","gaps":["Whether dietary modulation translates to patients not addressed","Distinct lipid effects on activation versus inactivation not fully separated mechanistically"]},{"year":2019,"claim":"Defined PIEZO1 as the osteogenic mechanosensor coupling mechanical loading to bone formation, and demonstrated pharmacological gain-of-function increases bone mass.","evidence":"Osteoblast/osteocyte-specific conditional knockouts, fluid shear assays, microgravity simulation, and in vivo Yoda1 administration","pmids":["31290742","31588901"],"confidence":"High","gaps":["Downstream transcriptional program in bone cells not fully resolved here","Relative contributions of osteoblasts versus osteocytes not separated"]},{"year":2020,"claim":"Showed PIEZO1 couples mechanosensing to paracrine ligand release, driving FGF1-dependent adipogenesis and microbial ssRNA-dependent serotonin production in the gut.","evidence":"Adipocyte- and intestinal-epithelium-specific conditional knockouts, FGF1/FGFR1 dissection, ssRNA ligand identification, and RNase A infusion","pmids":["32385276","32640190"],"confidence":"High","gaps":["How PIEZO1 detects ssRNA chemically versus mechanically not resolved","Generalizability of ligand-release coupling across tissues unclear"]},{"year":2021,"claim":"Implicated PIEZO1 in macrophage-mediated erythrocyte turnover and systemic iron metabolism via hepcidin control, with a common human GOF allele influencing plasma iron.","evidence":"Constitutive and macrophage-specific GOF knock-in mice with hepcidin and iron assays plus human genetic association","pmids":["33571427"],"confidence":"High","gaps":["Mechanism linking macrophage PIEZO1 activity to hepcidin not fully resolved","Causal mechanical input to macrophage PIEZO1 in vivo undefined"]},{"year":2022,"claim":"Resolved the structural basis of gating, showing tension-driven flattening of the curved channel quantitatively accounts for activation tension.","evidence":"Cryo-EM of PIEZO1 in liposomes capturing curved and flattened states with in-plane area and stiffness calculations","pmids":["35388220"],"confidence":"High","gaps":["Conformational pathway between states not kinetically resolved","Lipid and modifier binding sites not mapped in the structures"]},{"year":2022,"claim":"Mapped the molecular machinery directing PIEZO1 to endothelial junctions, identifying PECAM1 and shear-responsive CDH5 as direct partners while excluding VEGFR2.","evidence":"Native-tagged PIEZO1 mice, reconstitution, reciprocal co-IP, high-resolution colocalization, and shear stress assays","pmids":["37005489"],"confidence":"High","gaps":["Functional consequence of junctional targeting for channel gating not fully defined","Stoichiometry of PIEZO1-PECAM1/CDH5 complexes unknown"]},{"year":2022,"claim":"Expanded PIEZO1's vascular and inflammatory repertoire, defining its role in leukocyte diapedesis, capillary mechanosensing, lymphatic mechanotransduction, and mitochondrial OXPHOS.","evidence":"Endothelial/lymphatic conditional knockouts, capillary electrophysiology, Orai1 epistasis, phospho-signaling cascades, and Seahorse metabolic assays","pmids":["35443048","35382561","35701867","36052712"],"confidence":"High","gaps":["Multiple parallel downstream cascades not integrated into a single regulatory logic","Tissue-specific determinants of which effector is engaged unresolved"]},{"year":2023,"claim":"Revealed that PIEZO1 blades are more expanded at rest in native membranes than predicted, refining the relationship between blade conformation and channel state in living cells.","evidence":"Single-molecule nanoscopic fluorescence imaging of endogenously tagged PIEZO1 with chemical and mechanical modulators","pmids":["37587339"],"confidence":"High","gaps":["Quantitative link between blade expansion and open probability not established","Native-cell forces shaping resting curvature not measured directly"]},{"year":2023,"claim":"Defined quantitative biophysical gating thresholds in chondrocytes and established membrane stretch as the proximate gating stimulus.","evidence":"Single-cell AFM compression with finite element modeling, calcium imaging, and PIEZO1/2 knockout","pmids":["37459546"],"confidence":"High","gaps":["Translation of stretch ratio threshold to physiological joint loading unclear","Contribution of PIEZO2 versus PIEZO1 at lower strains not fully separated"]},{"year":2023,"claim":"Connected PIEZO1 to immune effector mechanics and named downstream signaling networks, including neutrophil NOX4 bactericidal activity, NETosis, EGFR-ERK activation, and lymphatic ANGPT2/TIE1 signaling.","evidence":"PMN-, neutrophil-, and lymphatic-targeted manipulation with intravital imaging, microfluidics, phospho-site analysis, and conditional knockouts","pmids":["38091995","39174529","37756411","38747287"],"confidence":"High","gaps":["Whether these cascades share a common proximal calcium-effector module is unresolved","Some signaling links derive from single-lab pharmacology"]},{"year":2024,"claim":"Identified TMEM16F as the PIEZO1-coupled phosphatidylserine scramblase in erythrocytes and defined PIEZO1 roles in adaptive and innate immune effector programs.","evidence":"Calcium/PS exposure assays in normal and HX RBCs, traction force microscopy in T cells, and ILC2/macrophage conditional knockouts","pmids":["38033286","38514773","38530239","38838160"],"confidence":"High","gaps":["Physical coupling between PIEZO1 and TMEM16F not structurally defined","Cell-type determinants selecting GRHL3/RNF114 versus KLF2 versus YAP outputs unclear"]},{"year":2025,"claim":"Extended PIEZO1 into fibrotic, metabolic, and aneurysmal disease, dissecting YAP/TAZ-dependent myofibroblast activation, calpain/Drp1 mitochondrial fission, and TGFBR2 trafficking via Rab3C.","evidence":"Cell-type-specific conditional knockouts with epistasis (Yap/Taz KO), TGFBR2 endocytosis/autophagy assays, and Yoda1 in vivo treatment","pmids":["40454481","40114130","39585648","39932793"],"confidence":"Medium","gaps":["Most disease mechanisms rest on single-lab studies","How a single channel selects opposing pro- versus anti-fibrotic outputs across cell types unresolved"]},{"year":null,"claim":"The unifying logic by which a single tension sensor is interpreted into divergent, sometimes opposing, cell-type-specific transcriptional and metabolic programs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No general model links calcium amplitude/kinetics to choice of downstream effector (Gardos, calpain, YAP, ERK, etc.)","Direct partners beyond PECAM1/CDH5 that route output are largely unmapped","Structural basis of chemical ligand (ssRNA) versus mechanical sensing not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,5,6,25,28]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,15,23,25]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7,15,18,23]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,19,24,42]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,19,27,32,34]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,9,10,12]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[16,25]}],"complexes":[],"partners":["PECAM1","CDH5","TMEM16F","KCNN4","ORAI1","TRPC6","RRAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92508","full_name":"Piezo-type mechanosensitive ion channel component 1","aliases":["Membrane protein induced by beta-amyloid treatment","Mib","Protein FAM38A"],"length_aa":2521,"mass_kda":286.8,"function":"Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain (PubMed:23479567, PubMed:23695678, PubMed:25955826, PubMed:37590348). Piezo channels are homotrimeric three-blade propeller-shaped structures that utilize a cap-motion and plug-and-latch mechanism to gate their ion-conducting pathways (PubMed:37590348). Generates currents characterized by a linear current-voltage relationship that are sensitive to ruthenium red and gadolinium (By similarity). Conductance to monovalent alkali ions is highest for K(+), intermediate for Na(+) and lowest for Li(+) (PubMed:25955826). Divalent ions except for Mn(2+) permeate the channel but more slowly than the monovalent ions and they also reduce K(+) currents (PubMed:25955826). Plays a key role in epithelial cell adhesion by maintaining integrin activation through R-Ras recruitment to the ER, most probably in its activated state, and subsequent stimulation of calpain signaling (PubMed:20016066). In inner ear hair cells, PIEZO1/2 subunits may constitute part of the mechanotransducer (MET) non-selective cation channel complex where they may act as pore-forming ion-conducting component in the complex (By similarity). In the kidney, may contribute to the detection of intraluminal pressure changes and to urine flow sensing (By similarity). Acts as a shear-stress sensor that promotes endothelial cell organization and alignment in the direction of blood flow through calpain activation (PubMed:25119035). Plays a key role in blood vessel formation and vascular structure in both development and adult physiology (By similarity). Acts as a sensor of phosphatidylserine (PS) flipping at the plasma membrane and governs morphogenesis of muscle cells (By similarity). In myoblasts, flippase-mediated PS enrichment at the inner leaflet of plasma membrane triggers channel activation and Ca2+ influx followed by Rho GTPases signal transduction, leading to assembly of cortical actomyosin fibers and myotube formation (PubMed:29799007)","subcellular_location":"Endoplasmic reticulum membrane; Endoplasmic reticulum-Golgi intermediate compartment membrane; Cell membrane; Cell projection, lamellipodium membrane","url":"https://www.uniprot.org/uniprotkb/Q92508/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIEZO1","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PIEZO1","total_profiled":1310},"omim":[{"mim_id":"621342","title":"TRANSMEMBRANE PROTEIN 87A; TMEM87A","url":"https://www.omim.org/entry/621342"},{"mim_id":"620207","title":"BLOOD GROUP, ER; ER","url":"https://www.omim.org/entry/620207"},{"mim_id":"617292","title":"TRANSMEMBRANE PROTEIN 150C; TMEM150C","url":"https://www.omim.org/entry/617292"},{"mim_id":"616843","title":"LYMPHATIC MALFORMATION 6; LMPHM6","url":"https://www.omim.org/entry/616843"},{"mim_id":"616689","title":"DEHYDRATED HEREDITARY STOMATOCYTOSIS 2; DHS2","url":"https://www.omim.org/entry/616689"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PIEZO1"},"hgnc":{"alias_symbol":["KIAA0233"],"prev_symbol":["FAM38A"]},"alphafold":{"accession":"Q92508","domains":[{"cath_id":"-","chopping":"4-144","consensus_level":"high","plddt":75.8562,"start":4,"end":144},{"cath_id":"-","chopping":"190-334","consensus_level":"medium","plddt":80.6686,"start":190,"end":334},{"cath_id":"-","chopping":"575-709","consensus_level":"medium","plddt":85.7008,"start":575,"end":709},{"cath_id":"-","chopping":"981-1062_1076-1135","consensus_level":"medium","plddt":89.2081,"start":981,"end":1135},{"cath_id":"-","chopping":"1148-1304","consensus_level":"medium","plddt":85.0754,"start":1148,"end":1304},{"cath_id":"-","chopping":"1656-1668_1675-1808","consensus_level":"medium","plddt":86.2646,"start":1656,"end":1808},{"cath_id":"-","chopping":"2204-2432","consensus_level":"medium","plddt":85.2072,"start":2204,"end":2432},{"cath_id":"1.20.1270","chopping":"803-885_913-961","consensus_level":"medium","plddt":88.1555,"start":803,"end":961}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92508","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92508-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92508-F1-predicted_aligned_error_v6.png","plddt_mean":72.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIEZO1","jax_strain_url":"https://www.jax.org/strain/search?query=PIEZO1"},"sequence":{"accession":"Q92508","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92508.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92508/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92508"}},"corpus_meta":[{"pmid":"20813920","id":"PMC_20813920","title":"Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20813920","citation_count":2442,"is_preprint":false},{"pmid":"24958852","id":"PMC_24958852","title":"Piezo1, a mechanically activated ion channel, is required for vascular development in mice.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24958852","citation_count":712,"is_preprint":false},{"pmid":"28199303","id":"PMC_28199303","title":"Mechanical stretch triggers rapid epithelial cell division through Piezo1.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28199303","citation_count":590,"is_preprint":false},{"pmid":"26001275","id":"PMC_26001275","title":"Chemical activation of the mechanotransduction channel Piezo1.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26001275","citation_count":575,"is_preprint":false},{"pmid":"26001274","id":"PMC_26001274","title":"Piezo1 links mechanical forces to red blood cell volume.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26001274","citation_count":501,"is_preprint":false},{"pmid":"21696149","id":"PMC_21696149","title":"The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21696149","citation_count":442,"is_preprint":false},{"pmid":"22529292","id":"PMC_22529292","title":"Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22529292","citation_count":363,"is_preprint":false},{"pmid":"31290742","id":"PMC_31290742","title":"The mechanosensitive Piezo1 channel is required for bone formation.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31290742","citation_count":322,"is_preprint":false},{"pmid":"31588901","id":"PMC_31588901","title":"Stimulation of Piezo1 by mechanical signals promotes bone anabolism.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31588901","citation_count":297,"is_preprint":false},{"pmid":"30867417","id":"PMC_30867417","title":"Dietary fatty acids fine-tune Piezo1 mechanical response.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30867417","citation_count":214,"is_preprint":false},{"pmid":"35388220","id":"PMC_35388220","title":"Structure deformation and curvature sensing of PIEZO1 in lipid membranes.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35388220","citation_count":213,"is_preprint":false},{"pmid":"36898371","id":"PMC_36898371","title":"Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis.","date":"2023","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/36898371","citation_count":198,"is_preprint":false},{"pmid":"33571427","id":"PMC_33571427","title":"A role of PIEZO1 in iron metabolism in mice and humans.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33571427","citation_count":184,"is_preprint":false},{"pmid":"20016066","id":"PMC_20016066","title":"Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/20016066","citation_count":177,"is_preprint":false},{"pmid":"34667178","id":"PMC_34667178","title":"Roles of mechanosensitive channel Piezo1/2 proteins in skeleton and other tissues.","date":"2021","source":"Bone research","url":"https://pubmed.ncbi.nlm.nih.gov/34667178","citation_count":167,"is_preprint":false},{"pmid":"34781417","id":"PMC_34781417","title":"Mechanosensing by Piezo1 and its implications for physiology and various pathologies.","date":"2021","source":"Biological reviews of the Cambridge Philosophical Society","url":"https://pubmed.ncbi.nlm.nih.gov/34781417","citation_count":146,"is_preprint":false},{"pmid":"35154133","id":"PMC_35154133","title":"Piezo1 Channels as Force Sensors in Mechanical Force-Related Chronic Inflammation.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35154133","citation_count":146,"is_preprint":false},{"pmid":"22792288","id":"PMC_22792288","title":"Loss of the integrin-activating transmembrane protein Fam38A (Piezo1) promotes a switch to a reduced integrin-dependent mode of cell migration.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22792288","citation_count":137,"is_preprint":false},{"pmid":"35963237","id":"PMC_35963237","title":"Astrocytic Piezo1-mediated mechanotransduction determines adult neurogenesis and cognitive functions.","date":"2022","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/35963237","citation_count":133,"is_preprint":false},{"pmid":"35230979","id":"PMC_35230979","title":"Mechanosensitive Piezo1 channels mediate renal fibrosis.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/35230979","citation_count":132,"is_preprint":false},{"pmid":"32640190","id":"PMC_32640190","title":"RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis.","date":"2020","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/32640190","citation_count":132,"is_preprint":false},{"pmid":"36181398","id":"PMC_36181398","title":"Activation of Piezo1 contributes to matrix stiffness-induced angiogenesis in hepatocellular carcinoma.","date":"2022","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36181398","citation_count":131,"is_preprint":false},{"pmid":"32385276","id":"PMC_32385276","title":"Adipocyte Piezo1 mediates obesogenic adipogenesis through the FGF1/FGFR1 signaling pathway in mice.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32385276","citation_count":126,"is_preprint":false},{"pmid":"37098060","id":"PMC_37098060","title":"The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37098060","citation_count":124,"is_preprint":false},{"pmid":"31166705","id":"PMC_31166705","title":"Expression and distribution of PIEZO1 in the mouse urinary tract.","date":"2019","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31166705","citation_count":116,"is_preprint":false},{"pmid":"37587339","id":"PMC_37587339","title":"Direct observation of the conformational states of PIEZO1.","date":"2023","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/37587339","citation_count":113,"is_preprint":false},{"pmid":"35706029","id":"PMC_35706029","title":"Microglial amyloid beta clearance is driven by PIEZO1 channels.","date":"2022","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/35706029","citation_count":109,"is_preprint":false},{"pmid":"28728825","id":"PMC_28728825","title":"Genetic Diseases of PIEZO1 and PIEZO2 Dysfunction.","date":"2017","source":"Current topics in membranes","url":"https://pubmed.ncbi.nlm.nih.gov/28728825","citation_count":108,"is_preprint":false},{"pmid":"35382561","id":"PMC_35382561","title":"Piezo1 Is a Mechanosensor Channel in Central Nervous System Capillaries.","date":"2022","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/35382561","citation_count":105,"is_preprint":false},{"pmid":"34669509","id":"PMC_34669509","title":"Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension.","date":"2021","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34669509","citation_count":95,"is_preprint":false},{"pmid":"38838160","id":"PMC_38838160","title":"Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38838160","citation_count":93,"is_preprint":false},{"pmid":"35443048","id":"PMC_35443048","title":"Mechanosensation by endothelial PIEZO1 is required for leukocyte diapedesis.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/35443048","citation_count":87,"is_preprint":false},{"pmid":"35701867","id":"PMC_35701867","title":"Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.","date":"2022","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/35701867","citation_count":79,"is_preprint":false},{"pmid":"35844802","id":"PMC_35844802","title":"Mechanosensitive Piezo1 is crucial for periosteal stem cell-mediated fracture healing.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35844802","citation_count":79,"is_preprint":false},{"pmid":"37005489","id":"PMC_37005489","title":"PIEZO1 and PECAM1 interact at cell-cell junctions and partner in endothelial force sensing.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37005489","citation_count":78,"is_preprint":false},{"pmid":"35417225","id":"PMC_35417225","title":"Myeloid Piezo1 Deletion Protects Renal Fibrosis by Restraining Macrophage Infiltration and Activation.","date":"2022","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/35417225","citation_count":77,"is_preprint":false},{"pmid":"34464353","id":"PMC_34464353","title":"Functional roles for PIEZO1 and PIEZO2 in urothelial mechanotransduction and lower urinary tract interoception.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34464353","citation_count":70,"is_preprint":false},{"pmid":"38395992","id":"PMC_38395992","title":"Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development.","date":"2024","source":"Bone research","url":"https://pubmed.ncbi.nlm.nih.gov/38395992","citation_count":68,"is_preprint":false},{"pmid":"37758057","id":"PMC_37758057","title":"Piezo1 activation accelerates osteoarthritis progression and the targeted therapy effect of artemisinin.","date":"2023","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/37758057","citation_count":67,"is_preprint":false},{"pmid":"38556840","id":"PMC_38556840","title":"Matrix stiffness regulates macrophage polarisation via the Piezo1-YAP signalling axis.","date":"2024","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/38556840","citation_count":65,"is_preprint":false},{"pmid":"35173527","id":"PMC_35173527","title":"Emerging Piezo1 signaling in inflammation and atherosclerosis; a potential therapeutic target.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35173527","citation_count":64,"is_preprint":false},{"pmid":"38091995","id":"PMC_38091995","title":"trans-Endothelial neutrophil migration activates bactericidal function via Piezo1 mechanosensing.","date":"2023","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/38091995","citation_count":62,"is_preprint":false},{"pmid":"28728823","id":"PMC_28728823","title":"Piezo1 Channels in Vascular Development and the Sensing of Shear Stress.","date":"2017","source":"Current topics in membranes","url":"https://pubmed.ncbi.nlm.nih.gov/28728823","citation_count":62,"is_preprint":false},{"pmid":"36053009","id":"PMC_36053009","title":"Keratinocyte PIEZO1 modulates cutaneous mechanosensation.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36053009","citation_count":61,"is_preprint":false},{"pmid":"37459546","id":"PMC_37459546","title":"Membrane stretch as the mechanism of activation of PIEZO1 ion channels in chondrocytes.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37459546","citation_count":59,"is_preprint":false},{"pmid":"38267432","id":"PMC_38267432","title":"Mechanical stiffness promotes skin fibrosis via Piezo1-Wnt2/Wnt11-CCL24 positive feedback loop.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38267432","citation_count":58,"is_preprint":false},{"pmid":"38514773","id":"PMC_38514773","title":"PIEZO1 mechanically regulates the antitumour cytotoxicity of T lymphocytes.","date":"2024","source":"Nature biomedical engineering","url":"https://pubmed.ncbi.nlm.nih.gov/38514773","citation_count":54,"is_preprint":false},{"pmid":"37908726","id":"PMC_37908726","title":"Piezo1 specific deletion in macrophage protects the progression of liver fibrosis in mice.","date":"2023","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/37908726","citation_count":54,"is_preprint":false},{"pmid":"37922791","id":"PMC_37922791","title":"Matrine induces ferroptosis in cervical cancer through activation of piezo1 channel.","date":"2023","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37922791","citation_count":54,"is_preprint":false},{"pmid":"31780935","id":"PMC_31780935","title":"Adenosine Triphosphate Release and P2 Receptor Signaling in Piezo1 Channel-Dependent Mechanoregulation.","date":"2019","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31780935","citation_count":54,"is_preprint":false},{"pmid":"34985971","id":"PMC_34985971","title":"PIEZO1 mediates a mechanothrombotic pathway in diabetes.","date":"2022","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34985971","citation_count":53,"is_preprint":false},{"pmid":"39174529","id":"PMC_39174529","title":"Piezo1 expression in neutrophils regulates shear-induced NETosis.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39174529","citation_count":50,"is_preprint":false},{"pmid":"37553778","id":"PMC_37553778","title":"Lepr-Expressing PDLSCs Contribute to Periodontal Homeostasis and Respond to Mechanical Force by Piezo1.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37553778","citation_count":50,"is_preprint":false},{"pmid":"39450718","id":"PMC_39450718","title":"Piezo1-Mediated Mechanotransduction Contributes to Disturbed Flow-Induced Atherosclerotic Endothelial Inflammation.","date":"2024","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/39450718","citation_count":44,"is_preprint":false},{"pmid":"36543525","id":"PMC_36543525","title":"Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation in ankylosing spondylitis.","date":"2022","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/36543525","citation_count":44,"is_preprint":false},{"pmid":"33848364","id":"PMC_33848364","title":"Recent advances in the pathophysiology of PIEZO1-related hereditary xerocytosis.","date":"2021","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/33848364","citation_count":38,"is_preprint":false},{"pmid":"38354960","id":"PMC_38354960","title":"Dexamethasone upregulates macrophage PIEZO1 via SGK1, suppressing inflammation and increasing ROS and apoptosis.","date":"2024","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38354960","citation_count":35,"is_preprint":false},{"pmid":"36751801","id":"PMC_36751801","title":"Piezo1 suppression reduces demyelination after intracerebral hemorrhage.","date":"2023","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/36751801","citation_count":35,"is_preprint":false},{"pmid":"39004029","id":"PMC_39004029","title":"Quercetin ameliorates atherosclerosis by inhibiting inflammation of vascular endothelial cells via Piezo1 channels.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39004029","citation_count":33,"is_preprint":false},{"pmid":"38530239","id":"PMC_38530239","title":"Piezo1 channels restrain ILC2s and regulate the development of airway hyperreactivity.","date":"2024","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38530239","citation_count":30,"is_preprint":false},{"pmid":"38033286","id":"PMC_38033286","title":"Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis.","date":"2024","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/38033286","citation_count":30,"is_preprint":false},{"pmid":"36368521","id":"PMC_36368521","title":"The role of mechanosensor Piezo1 in bone homeostasis and mechanobiology.","date":"2022","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36368521","citation_count":30,"is_preprint":false},{"pmid":"38702777","id":"PMC_38702777","title":"Ion channel Piezo1 activation aggravates the endothelial dysfunction under a high glucose environment.","date":"2024","source":"Cardiovascular diabetology","url":"https://pubmed.ncbi.nlm.nih.gov/38702777","citation_count":29,"is_preprint":false},{"pmid":"31754715","id":"PMC_31754715","title":"Amphipathic molecules modulate PIEZO1 activity.","date":"2019","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/31754715","citation_count":29,"is_preprint":false},{"pmid":"37349903","id":"PMC_37349903","title":"Independent endothelial functions of PIEZO1 and TRPV4 in hepatic portal vein and predominance of PIEZO1 in mechanical and osmotic stress.","date":"2023","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/37349903","citation_count":29,"is_preprint":false},{"pmid":"39402010","id":"PMC_39402010","title":"Pharmacology of PIEZO1 channels.","date":"2024","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39402010","citation_count":28,"is_preprint":false},{"pmid":"38959010","id":"PMC_38959010","title":"The chondrocyte \"mechanome\": Activation of the mechanosensitive ion channels TRPV4 and PIEZO1 drives unique transcriptional signatures.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/38959010","citation_count":28,"is_preprint":false},{"pmid":"37867255","id":"PMC_37867255","title":"Actomyosin Activity and Piezo1 Activity Synergistically Drive Urinary System Fibroblast Activation.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37867255","citation_count":27,"is_preprint":false},{"pmid":"34349540","id":"PMC_34349540","title":"Mechanosensitive Piezo1 Channel Evoked-Mechanical Signals in Atherosclerosis.","date":"2021","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/34349540","citation_count":27,"is_preprint":false},{"pmid":"40454481","id":"PMC_40454481","title":"PIEZO1 mediates periostin+ myofibroblast activation and pulmonary fibrosis in mice.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/40454481","citation_count":25,"is_preprint":false},{"pmid":"39932793","id":"PMC_39932793","title":"PIEZO1-Mediated Calcium Signaling and Podocyte Injury in Diabetic Kidney Disease.","date":"2025","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/39932793","citation_count":25,"is_preprint":false},{"pmid":"39216559","id":"PMC_39216559","title":"Epithelial Piezo1 deletion ameliorates intestinal barrier damage by regulating ferroptosis in ulcerative colitis.","date":"2024","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39216559","citation_count":25,"is_preprint":false},{"pmid":"38467889","id":"PMC_38467889","title":"Gastric mechanosensitive channel Piezo1 regulates ghrelin production and food intake.","date":"2024","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38467889","citation_count":25,"is_preprint":false},{"pmid":"37259842","id":"PMC_37259842","title":"Piezo1 Mediates Vasodilation Induced by Acute Hyperglycemia in Mouse Renal Arteries and Microvessels.","date":"2023","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/37259842","citation_count":25,"is_preprint":false},{"pmid":"38271270","id":"PMC_38271270","title":"Long-term simulated microgravity fosters carotid aging-like changes via Piezo1.","date":"2024","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/38271270","citation_count":25,"is_preprint":false},{"pmid":"35436566","id":"PMC_35436566","title":"The role of mechanosensitive Piezo1 channel in diseases.","date":"2022","source":"Progress in biophysics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35436566","citation_count":24,"is_preprint":false},{"pmid":"38575957","id":"PMC_38575957","title":"Intestinal Piezo1 aggravates intestinal barrier dysfunction during sepsis by mediating Ca2+ influx.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38575957","citation_count":23,"is_preprint":false},{"pmid":"38747287","id":"PMC_38747287","title":"The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38747287","citation_count":23,"is_preprint":false},{"pmid":"37147884","id":"PMC_37147884","title":"Piezo1 opposes age-associated cortical bone loss.","date":"2023","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/37147884","citation_count":23,"is_preprint":false},{"pmid":"36052712","id":"PMC_36052712","title":"Piezo1 stimulates mitochondrial function via cAMP signaling.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36052712","citation_count":23,"is_preprint":false},{"pmid":"37756411","id":"PMC_37756411","title":"Piezo1 activates noncanonical EGFR endocytosis and signaling.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37756411","citation_count":22,"is_preprint":false},{"pmid":"39978573","id":"PMC_39978573","title":"Elevated expression of Piezo1 activates the cGAS-STING pathway in chondrocytes by releasing mitochondrial DNA.","date":"2025","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/39978573","citation_count":21,"is_preprint":false},{"pmid":"39107572","id":"PMC_39107572","title":"PIEZO1 targeting in macrophages boosts phagocytic activity and foam cell apoptosis in atherosclerosis.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39107572","citation_count":21,"is_preprint":false},{"pmid":"40181773","id":"PMC_40181773","title":"Piezo1 in PASMCs: Critical for Hypoxia-Induced Pulmonary Hypertension Development.","date":"2025","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/40181773","citation_count":20,"is_preprint":false},{"pmid":"33465396","id":"PMC_33465396","title":"Piezo1 plays a role in optic nerve head astrocyte reactivity.","date":"2021","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/33465396","citation_count":20,"is_preprint":false},{"pmid":"38581527","id":"PMC_38581527","title":"Piezo1, the new actor in cell volume regulation.","date":"2024","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38581527","citation_count":20,"is_preprint":false},{"pmid":"40750459","id":"PMC_40750459","title":"Piezo1: structural pharmacology and mechanotransduction mechanisms.","date":"2025","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40750459","citation_count":19,"is_preprint":false},{"pmid":"37184045","id":"PMC_37184045","title":"Piezo1 mediates the degradation of cartilage extracellular matrix in malocclusion-induced TMJOA.","date":"2023","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37184045","citation_count":19,"is_preprint":false},{"pmid":"37722629","id":"PMC_37722629","title":"Piezo1：the potential new therapeutic target for fibrotic diseases.","date":"2023","source":"Progress in biophysics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37722629","citation_count":19,"is_preprint":false},{"pmid":"40114130","id":"PMC_40114130","title":"Piezo1 deletion mitigates diabetic cardiomyopathy by maintaining mitochondrial dynamics via ERK/Drp1 pathway.","date":"2025","source":"Cardiovascular diabetology","url":"https://pubmed.ncbi.nlm.nih.gov/40114130","citation_count":18,"is_preprint":false},{"pmid":"39585648","id":"PMC_39585648","title":"PIEZO1 attenuates Marfan syndrome aneurysm development through TGF-β signaling pathway inhibition via TGFBR2.","date":"2025","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/39585648","citation_count":18,"is_preprint":false},{"pmid":"39890818","id":"PMC_39890818","title":"Piezo1-directed neutrophil extracellular traps regulate macrophage differentiation during influenza virus infection.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39890818","citation_count":18,"is_preprint":false},{"pmid":"38126029","id":"PMC_38126029","title":"Piezo1 facilitates optimal T cell activation during tumor challenge.","date":"2023","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/38126029","citation_count":18,"is_preprint":false},{"pmid":"38338996","id":"PMC_38338996","title":"Mechanosensitive Cation Channel Piezo1 Is Involved in Renal Fibrosis Induction.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38338996","citation_count":18,"is_preprint":false},{"pmid":"37582313","id":"PMC_37582313","title":"Piezo1 in skin wound healing and related diseases: Mechanotransduction and therapeutic implications.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37582313","citation_count":17,"is_preprint":false},{"pmid":"35846568","id":"PMC_35846568","title":"Expression of Piezo1 in the Trigeminal Neurons and in the Axons That Innervate the Dental Pulp.","date":"2022","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35846568","citation_count":17,"is_preprint":false},{"pmid":"37717661","id":"PMC_37717661","title":"PIEZO1 expression at the glio-vascular unit adjusts to neuroinflammation in seizure conditions.","date":"2023","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/37717661","citation_count":16,"is_preprint":false},{"pmid":"40129609","id":"PMC_40129609","title":"Targeting Piezo1 channel to alleviate intervertebral disc degeneration.","date":"2025","source":"Journal of orthopaedic translation","url":"https://pubmed.ncbi.nlm.nih.gov/40129609","citation_count":16,"is_preprint":false},{"pmid":"38619396","id":"PMC_38619396","title":"Piezo1 and Piezo2 collectively regulate jawbone development.","date":"2024","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38619396","citation_count":16,"is_preprint":false},{"pmid":"38316716","id":"PMC_38316716","title":"Role of mechanically-sensitive cation channels Piezo1 and TRPV4 in trabecular meshwork cell mechanotransduction.","date":"2024","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/38316716","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49828,"output_tokens":11780,"usd":0.163092,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23346,"output_tokens":6034,"usd":0.13379,"stage2_stop_reason":"end_turn"},"total_usd":0.296882,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Piezo1 (Fam38A) is an essential component of a mechanically activated (MA) cation channel. RNA interference knockdown of Piezo1 eliminated rapidly adapting MA currents in a mouse neuroblastoma cell line, and overexpression of mouse Piezo1 induced a kinetically distinct MA current, establishing Piezo1 as a pore-forming component of an MA cation channel.\",\n      \"method\": \"RNAi knockdown, overexpression, whole-cell and outside-out patch-clamp electrophysiology\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct electrophysiological reconstitution with gain- and loss-of-function in the same study; foundational paper replicated extensively\",\n      \"pmids\": [\"20813920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The peptide GsMTx4 reversibly inhibits Piezo1-mediated mechanically activated currents in outside-out and whole-cell configurations, acting as a gating modifier (voltage-insensitive, active on closed channels) that shifts the pressure-gating curve ~30 mmHg rightward, with KD ~155 nM. The d-enantiomer was equally effective, consistent with membrane-mediated inhibition rather than stereospecific binding.\",\n      \"method\": \"Outside-out and whole-cell patch-clamp electrophysiology in HEK293 cells overexpressing Piezo1; kinetic rate-constant analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative electrophysiological characterization with pressure-gating curves, enantiomer controls, and rate-constant analysis in a single rigorous study\",\n      \"pmids\": [\"21696149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fam38A/Piezo1 localizes to the endoplasmic reticulum (ER) and activates integrin-ligand affinity by recruiting the small GTPase R-Ras to the ER, which increases Ca2+ release from cytoplasmic stores, activates calpain, and leads to talin cleavage. siRNA knockdown of Fam38A inactivates β1 integrin and reduces cell adhesion; this pathway is blocked by inhibition of R-Ras, calpain, or talin knockdown.\",\n      \"method\": \"siRNA knockdown, subcellular fractionation/immunofluorescence localization to ER, cell adhesion assays, pharmacological inhibition of R-Ras and calpain, co-immunoprecipitation\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (localization, knockdown, pharmacological inhibition, epistasis) in a single lab; ER localization finding is distinct from later plasma-membrane mechanosensing studies\",\n      \"pmids\": [\"20016066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Gain-of-function mutations in PIEZO1 (FAM38A) cause hereditary xerocytosis (HX), an autosomal dominant hemolytic anemia with primary erythrocyte dehydration. PIEZO1 peptides were identified by discovery proteomics in human erythrocyte membranes, establishing Piezo1 as an endogenous erythrocyte membrane protein.\",\n      \"method\": \"Copy number analysis, linkage studies, exome sequencing, segregation analysis, discovery proteomics of erythrocyte membranes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — human genetics with segregation in two kindreds, proteomics confirmation of protein in erythrocyte membrane; independently replicated by subsequent studies\",\n      \"pmids\": [\"22529292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Piezo1 is expressed in endothelial cells of developing blood vessels and is activated by shear stress. Endothelial-specific Piezo1 deletion is embryonic lethal with vascular remodeling defects, and loss of Piezo1 impairs shear-stress-induced stress fiber formation and cell orientation, linking Piezo1 mechanotransduction to regulation of endothelial cell morphology.\",\n      \"method\": \"Conditional endothelial-specific knockout mice, shear stress application, cell orientation and stress fiber assays, in vivo vascular phenotyping\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endothelial-specific genetic deletion with defined embryonic lethal vascular phenotype, shear stress activation confirmed, cellular morphology readout; replicated by multiple subsequent labs\",\n      \"pmids\": [\"24958852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Yoda1, a synthetic small molecule identified by screening ~3.25 million compounds, acts as a chemical agonist for both human and mouse Piezo1, affecting sensitivity and inactivation kinetics of mechanically induced responses. Yoda1 activates purified Piezo1 channels reconstituted in artificial droplet lipid bilayers in the absence of other cellular components, demonstrating direct channel activation.\",\n      \"method\": \"Cell-based fluorescence screening, electrophysiology, reconstitution of purified Piezo1 in droplet lipid bilayers\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct reconstitution of purified channel in lipid bilayers with small-molecule agonist; independently used as tool compound by dozens of subsequent labs\",\n      \"pmids\": [\"26001275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Red blood cells exhibit Piezo1-dependent calcium entry in response to mechanical stretch. RBC-specific Piezo1 conditional knockout produces overhydrated, fragile RBCs. Piezo1 activation by Yoda1 causes calcium influx and subsequent RBC dehydration via downstream activation of the KCa3.1 Gardos channel, establishing the Piezo1→Gardos channel axis for RBC volume control.\",\n      \"method\": \"RBC-specific conditional knockout mice, calcium imaging, RBC fragility assays (in vitro and in vivo), Yoda1 pharmacology, Gardos channel pharmacological dissection\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with cellular phenotype, pharmacological dissection of downstream pathway, multiple orthogonal methods; replicated by subsequent hereditary xerocytosis studies\",\n      \"pmids\": [\"26001274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mechanical stretch stimulates epithelial cell division through Piezo1. Stretch triggers cells paused in early G2 to activate calcium-dependent phosphorylation of ERK1/2, activating cyclin B transcription to drive mitosis. Piezo1 subcellular localization differs with cell density: in sparse (dividing) regions it localizes to the plasma membrane and cytoplasm, while in dense (extruding) regions it forms large cytoplasmic aggregates.\",\n      \"method\": \"Mechanical stretch of epithelia, calcium imaging, phospho-ERK assays, cyclin B reporter assays, Piezo1 knockdown, live-cell imaging of Piezo1 localization\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (stretch, knockdown, signaling assays, live localization imaging) in a single rigorous study establishing mechanism\",\n      \"pmids\": [\"28199303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dietary fatty acids tune Piezo1 mechanical response: margaric acid (a saturated fatty acid) inhibits Piezo1 activation by increasing membrane bending stiffness, whereas polyunsaturated fatty acids (PUFAs) modulate channel inactivation by decreasing membrane bending stiffness. Fatty acid supplementation can abrogate gain-of-function Piezo1 mutation phenotypes.\",\n      \"method\": \"Lipid profiling, electrophysiology, atomic force microscopy membrane stiffness measurements, fatty acid supplementation in gain-of-function Piezo1 mutant cells\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology combined with direct membrane stiffness measurements and functional rescue of disease mutation phenotypes; multiple orthogonal methods in one study\",\n      \"pmids\": [\"30867417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Piezo1 is required for bone formation by osteoblasts: knockout of Piezo1 in osteoblast lineage cells disrupts osteogenesis and impairs bone structure and strength, and simulated microgravity suppresses Piezo1 expression in osteoblasts to reduce their function.\",\n      \"method\": \"Osteoblast-lineage-specific conditional knockout mice, bone histology and biomechanical testing, microgravity simulation, gene expression analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional cell-type-specific knockout with defined bone phenotype; replicated by independent group (PMID 31588901)\",\n      \"pmids\": [\"31290742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Piezo1 mediates fluid shear stress-induced gene expression changes in osteocytes, and conditional deletion of Piezo1 in osteoblasts and osteocytes reduces bone mass and strength. Administration of a Piezo1 agonist (Yoda1) to adult mice increases bone mass, mimicking mechanical loading.\",\n      \"method\": \"Fluid shear stress assays in cultured osteocytes, conditional knockout mice, in vivo Yoda1 administration, bone mass and strength measurements\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic deletion plus pharmacological gain-of-function in vivo; replicates and extends PMID 31290742\",\n      \"pmids\": [\"31588901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Piezo1 activation leads to ATP release from cells, which acts as an autocrine/paracrine signal activating P2 purinergic receptors to regulate cell functions. Piezo1-mediated mechanotransduction thus couples mechanical stimulation to downstream purinergic signaling.\",\n      \"method\": \"ATP release assays, P2 receptor pharmacology, Piezo1 knockdown/activation experiments across multiple cell types\",\n      \"journal\": \"Frontiers in Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — review synthesizing multiple experimental findings from multiple labs, but original experimental evidence cited is indirect; single mechanistic claim supported by referenced primary studies\",\n      \"pmids\": [\"31780935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Piezo1 in mature adipocytes mediates diet-induced adipogenesis by releasing adipogenic fibroblast growth factor 1 (FGF1) upon channel opening, which induces adipocyte precursor differentiation through activation of FGF receptor 1. Mice lacking Piezo1 in mature adipocytes show defective preadipocyte differentiation on high-fat diet.\",\n      \"method\": \"Mature adipocyte-specific conditional Piezo1 knockout mice, high-fat diet challenge, FGF1 measurement, FGFR1 pharmacological inhibition, adipogenesis assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with dietary challenge, ligand identification (FGF1), receptor pharmacological dissection; multiple orthogonal methods\",\n      \"pmids\": [\"32385276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Gut Piezo1 in enterochromaffin cells functions as a sensor for single-stranded RNA (ssRNA) from fecal microbiota, governing serotonin (5-HT) production. Intestinal epithelium-specific Piezo1 deletion profoundly disturbs gut peristalsis and suppresses serum 5-HT levels. Colonic infusion of RNase A suppressed gut motility and increased bone mass, confirming the ssRNA–Piezo1 axis.\",\n      \"method\": \"Intestinal epithelium-specific conditional Piezo1 knockout, fecal ssRNA identification as ligand, RNase A infusion experiments, calcium imaging, bone mass measurement\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined phenotype, identification of ssRNA as natural ligand, orthogonal RNase A experiment, multiple readouts\",\n      \"pmids\": [\"32640190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Piezo1 is a key regulator of macrophage phagocytic activity and erythrocyte turnover, controlling hepcidin levels and iron metabolism. Constitutive or macrophage-specific expression of a gain-of-function Piezo1 allele in mice causes iron overload, and the E756del allele (present in ~1/3 of individuals of African descent) is strongly associated with increased plasma iron.\",\n      \"method\": \"Constitutive and macrophage-specific conditional knock-in of GOF Piezo1 allele in mice, hepcidin measurement, erythrocyte turnover assays, human genetic association in African Americans\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional macrophage-specific GOF allele in mice with defined hepcidin and iron phenotype, human genetic validation; multiple orthogonal approaches\",\n      \"pmids\": [\"33571427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM of PIEZO1 reconstituted in liposome vesicles revealed curved (resting) and flattened (activated) structural states. Membrane tension induces flattening of the blade (~300 nm2 in-plane area expansion), bending of the beam, and detaching/rotating of the cap, collectively gating the ion-conducting pathway. The calculated half-maximal activation tension (~1.9 pN/nm) matches experimental values.\",\n      \"method\": \"Cryo-EM structural determination of Piezo1 in liposomes, in-plane area and stiffness calculations, comparison with detergent-solubilized structures\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures in lipid bilayer with functional validation via matching calculated and experimental gating tensions; rigorous structural study\",\n      \"pmids\": [\"35388220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lipid peroxidation during ferroptosis increases plasma membrane tension, activating Piezo1 and TRP channels, causing cation permeability (Na+/Ca2+ influx, K+ efflux). Piezo1 deletion reduces these cation permeability changes. Oxidized lipids also depress Na+/K+-ATPase activity, and preventing cation content changes attenuates ferroptosis.\",\n      \"method\": \"Piezo1 deletion, calcium/sodium/potassium flux measurements, ruthenium red/2-APB channel blockers, ferroptosis induction (GPX4 inhibition), membrane tension measurement\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion of Piezo1 with pharmacological confirmation, direct membrane tension measurements, multiple ion flux readouts establishing mechanism\",\n      \"pmids\": [\"36898371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Astrocytic Piezo1 mediates mechanically evoked Ca2+ responses and ATP release (mechano-chemo transduction). Piezo1 deletion in astrocytes severely impairs adult hippocampal neurogenesis and abolishes ATP-dependent potentiation of neural stem cell proliferation. Overexpression of Piezo1 in astrocytes enhances LTP and learning/memory performance.\",\n      \"method\": \"Astrocyte-specific conditional knockout, in vivo neurogenesis assays, hippocampal LTP recordings, behavioral tests, ATP release measurement, Piezo1 overexpression\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation (knockout and overexpression) with multiple orthogonal mechanistic readouts (Ca2+, ATP, neurogenesis, LTP, behavior)\",\n      \"pmids\": [\"35963237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PECAM1 interacts with PIEZO1 and directs it to endothelial cell-cell junctions. PECAM1 extracellular N-terminus is critical for this interaction; CDH5 also drives PIEZO1 to junctions but its interaction is dynamic and increases with shear stress. PIEZO1 does not interact with VEGFR2. PIEZO1 is required for Ca2+-dependent formation of adherens junctions and associated cytoskeleton.\",\n      \"method\": \"Non-disruptive tagging of native PIEZO1 in mice, reconstitution experiments, high-resolution co-localization microscopy, co-immunoprecipitation, shear stress experiments, adherens junction assays\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — native-tagged protein in mice, reconstitution, reciprocal Co-IP, high-resolution microscopy; multiple orthogonal methods in one study\",\n      \"pmids\": [\"37005489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endothelial PIEZO1 mediates leukocyte diapedesis: leukocyte-induced clustering of ICAM-1 synergizes with fluid shear stress to increase endothelial membrane tension and activate PIEZO1, elevating [Ca2+]i and driving phosphorylation of SRC, PYK2, and myosin light chain, opening the endothelial barrier. Endothelium-specific Piezo1 deficiency reduces leukocyte extravasation in vivo.\",\n      \"method\": \"Endothelial-specific conditional knockout mice, Ca2+ imaging, phospho-SRC/PYK2/MLC measurements, in vivo inflammation models, ICAM-1 clustering assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional endothelial knockout with in vivo phenotype, defined signaling cascade with multiple phosphorylation readouts, mechanistic dissection of ICAM-1/shear stress synergy\",\n      \"pmids\": [\"35443048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Piezo1 activation by matrix stiffness in macrophages promotes M1 polarization via the YAP signaling axis. Increased matrix stiffness upregulates Piezo1 expression and activates YAP, favoring M1 and suppressing M2 polarization. YAP inhibitor treatment re-polarizes macrophages to M2.\",\n      \"method\": \"Polyacrylamide gels of varying stiffness, Piezo1 expression analysis, YAP activation assays, pharmacological YAP inhibition, macrophage polarization markers, in vivo implant model\",\n      \"journal\": \"Cell Proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, defined substrate stiffness system with YAP pathway dissection, but signaling link between Piezo1 and YAP not fully mechanistically resolved\",\n      \"pmids\": [\"38556840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Piezo1 activation in renal proximal tubular cells by mechanical stretch, compression, or matrix stiffness causes calcium influx, activates calpain2, cleaves talin1, and upregulates integrin β1, driving profibrotic responses. TGF-β1 also upregulates Piezo1 expression to drive profibrotic changes via this pathway.\",\n      \"method\": \"HK2 cells and primary mouse proximal tubular cells under mechanical stimulation, Yoda1 pharmacology, Piezo1 siRNA/inhibitor, calpain2 activity assay, talin1 cleavage by western blot, integrin β1 assay, UUO/folic acid mouse models with GsMTx4 treatment\",\n      \"journal\": \"JCI Insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro mechanistic dissection with multiple pathway components (calcium/calpain2/talin1/integrin β1) combined with in vivo mouse fibrosis models and pharmacological intervention\",\n      \"pmids\": [\"35230979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Piezo1 activation promotes Yap/Taz nuclear localization in periosteal stem cells, which in turn increases β-catenin nuclear localization. YAP directly interacts with β-catenin in the nucleus forming a transcriptional YAP/β-catenin complex that upregulates osteogenic, chondrogenic, and angiogenic factors including VEGF-A.\",\n      \"method\": \"Piezo1 agonist Yoda1 treatment of periosteal stem cells, YAP nuclear localization imaging, co-immunoprecipitation of YAP and β-catenin, gene expression assays, conditional knockout mice, fracture healing mouse model\",\n      \"journal\": \"International Journal of Biological Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of YAP/β-catenin, nuclear localization imaging, genetic and pharmacological manipulation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35844802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Direct nanoscopic fluorescence imaging of PIEZO1 in living cells revealed that blades are significantly expanded at rest by plasma membrane bending stress, more so than predicted from detergent-solubilized structures. Blade expansion correlates with channel activation, and blade flexibility varies along its length due to decreased inter-subdomain binding strength.\",\n      \"method\": \"Single-molecule nanoscopic fluorescence imaging (dSTORM/PAINT) of endogenously tagged PIEZO1 in live cells, chemical and mechanical modulators of channel activity\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — novel single-molecule structural approach in native cellular context with functional correlations; rigorous study with multiple modulators\",\n      \"pmids\": [\"37587339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Piezo1 provides the mechanistic link between mechanical signals and EGFR-ERK activation. Piezo1 activation triggers clathrin-mediated EGFR endocytosis and ERK activation via Src-p38 kinase-dependent serine phosphorylation of EGFR (not canonical EGF-induced tyrosine autophosphorylation). This Piezo1-dependent pathway promotes nuclear ERK, AP-1 (FOS/JUN), and YAP accumulation.\",\n      \"method\": \"Piezo1 agonist/antagonist pharmacology, EGFR endocytosis assays, phosphorylation site analysis (serine vs tyrosine), Src and p38 inhibitors, nuclear ERK/AP-1/YAP imaging, ex vivo lung slice experiments\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (endocytosis assays, phospho-site analysis, kinase inhibitors), single lab; mechanistic distinction from canonical EGF pathway well supported\",\n      \"pmids\": [\"37756411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Membrane stretch (detected by AFM with FEM modeling) is the mechanism of PIEZO1 gating in chondrocytes. PIEZO1 drives Ca2+ signaling independently at the highest strains, and factors increasing apparent membrane tension (hypoosmotic prestrain, high compression, low deformation rates) increase PIEZO1-driven Ca2+ signaling. The threshold membrane stretch ratio for PIEZO1 activation is λ=1.9.\",\n      \"method\": \"Single-cell AFM compression, finite element modeling, calcium imaging, PIEZO1/2 knockout chondrocytes, hypoosmotic treatment, pharmacological channel blockers\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — AFM+FEM biophysical characterization with genetic knockout, defines quantitative biophysical gating threshold; rigorous multi-method study\",\n      \"pmids\": [\"37459546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIEZO1 activation in lymphatic endothelial cells by fluid flow causes rapid exocytosis of ANGPT2, ectodomain shedding of TIE1 by ADAM17, and increased TIE/PI3K/AKT signaling, followed by nuclear export of the transcription factor FOXO1, establishing a functional molecular network linking PIEZO1 mechanosensing to transcriptional regulation in lymphatic vessels.\",\n      \"method\": \"Piezo1 activation/inhibition in cultured LECs, ANGPT2 exocytosis assays, TIE1 shedding assays (ADAM17 involvement), PI3K/AKT/FOXO1 signaling analysis, conditional knockout mice\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined multi-step signaling cascade (PIEZO1→ANGPT2 exocytosis→ADAM17/TIE1 shedding→PI3K/AKT→FOXO1) with genetic and pharmacological dissection\",\n      \"pmids\": [\"38747287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Piezo1 activation in neutrophils during trans-endothelial migration generates spike-like Ca2+ signals, upregulates NADPH oxidase 4 (NOX4), and enhances bactericidal function. PMN-specific Piezo1 deletion impairs bacterial clearance in vivo. Mechanical forces in microfluidic systems recapitulate Piezo1-dependent NOX4 upregulation and bactericidal activation.\",\n      \"method\": \"Piezo1-specific conditional knockout in PMNs, intravital imaging, calcium imaging, microfluidic systems, NOX4 expression assays, in vivo bacterial infection models, adoptive transfer experiments\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic knockout, microfluidic mechanical recapitulation, in vivo infection model, adoptive transfer; multiple orthogonal methods across two platforms\",\n      \"pmids\": [\"38091995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Piezo1 channels in brain capillary endothelial cells function as mechanosensors: activation by mechanical forces evokes Ca2+ signals in capillary endothelial cells, and these currents are absent upon endothelial cell-specific Piezo1 deletion.\",\n      \"method\": \"Electrophysiology of brain cortical and retinal capillaries, endothelial-specific Piezo1 deletion, genetically encoded Ca2+ indicator mice, ex vivo pressurized retina preparation\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — electrophysiological confirmation in native capillaries, genetic deletion specificity control, live Ca2+ imaging in pressurized retina preparation\",\n      \"pmids\": [\"35382561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Piezo1 activation increases intracellular Ca2+ in shear-stressed neutrophils, mediating calpain activity and cytoskeleton remodeling, which consequently induces NETosis. Shear-stress-induced NETosis is dependent on Piezo1 expression and is enhanced by NETosis-inducing agents.\",\n      \"method\": \"Microfluidics shear stress application, Piezo1 knockdown/overexpression, calcium imaging, calpain activity assays, cytoskeleton imaging, NET quantification\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (microfluidics, calcium, calpain, cytoskeleton), single lab, defined mechanistic pathway\",\n      \"pmids\": [\"39174529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Piezo1 in gastric X/A-like cells senses gastric distention and inhibits ghrelin production through the CaMKKII/CaMKIV-mTOR signaling pathway. X/A-like cell-specific Piezo1 knockout causes hyperghrelinemia, hyperphagia, and susceptibility to overweight; Piezo1 activation by Yoda1 or gastric bead implantation inhibits ghrelin production and decreases food intake.\",\n      \"method\": \"X/A-like cell-specific conditional Piezo1 knockout, Yoda1 pharmacology, gastric bead implantation, ghrelin measurements, CaMKKII/CaMKIV/mTOR pathway analysis in mHypoE-42 cell line\",\n      \"journal\": \"Nature Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockout with in vivo metabolic phenotypes, orthogonal mechanical activation (bead implantation), defined signaling cascade in relevant cell line\",\n      \"pmids\": [\"38467889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIEZO1 activation in red blood cells triggers Ca2+ influx through PIEZO1, which activates TMEM16F (the long-sought-after RBC phosphatidylserine scramblase). PIEZO1-TMEM16F functional coupling is enhanced in hereditary xerocytosis RBCs with PIEZO1 gain-of-function mutations, leading to increased PS exposure. GsMTx-4 and benzbromarone inhibit PIEZO1 and prevent force-induced PS exposure and hemolysis.\",\n      \"method\": \"Calcium influx assays, PS exposure assays, TMEM16F functional coupling in normal and HX patient RBCs, pharmacological inhibition with GsMTx-4 and benzbromarone, echinocytosis/hemolysis assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional coupling between PIEZO1 and TMEM16F established in human disease RBCs with pharmacological dissection; multiple mechanistic readouts\",\n      \"pmids\": [\"38033286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIEZO1 in cytotoxic T cells upregulates the transcription factor GRHL3, which induces expression of the E3 ubiquitin ligase RNF114. RNF114 binds to filamentous actin causing its downregulation and rearrangement, depressing traction forces in T cells. Blocking PIEZO1 strengthens traction forces and augments cytotoxicity against tumor cells.\",\n      \"method\": \"PIEZO1 knockout/antagonist treatment of cytotoxic T cells, traction force microscopy, GRHL3/RNF114 expression analysis, F-actin imaging, tumor killing assays, in vivo tumor model with adoptive T cell transfer\",\n      \"journal\": \"Nature Biomedical Engineering\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined PIEZO1→GRHL3→RNF114→F-actin→traction force pathway with multiple orthogonal methods, in vivo validation\",\n      \"pmids\": [\"38514773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Macrophage Piezo1 promotes progression of liver fibrosis by activating the Ca2+-dependent calpain protease, which drives CTSS (cathepsin S) secretion via cleavage of lysosome-associated membrane protein-1 (LAMP1). Myeloid-specific Piezo1 knockout reduces macrophage inflammation, CTSS secretion, and liver fibrosis.\",\n      \"method\": \"Myeloid-specific conditional Piezo1 knockout mice, RNA-seq, CTSS activity assays, calpain inhibition, LAMP1 cleavage western blot, liver fibrosis models (CCl4/BDL)\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with RNA-seq pathway identification, mechanistic LAMP1 cleavage assay, pharmacological calpain inhibition; single lab\",\n      \"pmids\": [\"37908726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Piezo1 in ILC2s restrains group 2 innate lymphoid cell-driven type 2 lung inflammation. Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner by reducing ILC2 oxidative metabolism. Genetic ablation of Piezo1 in ILC2s exacerbates airway hyperreactivity.\",\n      \"method\": \"ILC2-specific conditional Piezo1 knockout mice, Yoda1 pharmacology, cytokine secretion assays, proliferation assays, KLF2 knockdown, metabolic assays (oxidative phosphorylation), in vivo AHR models, humanized mouse models\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional cell-type-specific knockout, pharmacological activation, KLF2-dependency established, human ILC2 validation, multiple orthogonal methods\",\n      \"pmids\": [\"38530239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Disturbed flow activates Piezo1 in endothelial cells, causing Ca2+ influx that activates the CaM/CaMKII pathway, which phosphorylates FAK and Src, activating YAP and triggering endothelial inflammation. GsMTx4 inhibition of Piezo1 delays atherosclerotic plaque progression.\",\n      \"method\": \"Oscillatory shear stress application, Ca2+ imaging, pharmacological inhibition (GsMTx4, CaMKII inhibitor), FAK/Src/YAP phosphorylation assays, ApoE-/- atherosclerosis mouse model\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined Ca2+/CaM/CaMKII/FAK/Src/YAP cascade with pharmacological dissection and in vivo plaque model; single lab\",\n      \"pmids\": [\"39450718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Macrophage Piezo1 activation promotes efferocytosis on rigid substrates and facilitates efficient acidification of engulfed cargo in phagolysosomes, driving anti-inflammatory gene expression after efferocytosis. Macrophage-specific Piezo1 knockout impairs efferocytosis and spontaneous resolution of early liver fibrosis.\",\n      \"method\": \"Macrophage-specific conditional Piezo1 knockout, polyacrylamide gel stiffness assays, phagolysosomal acidification assays, anti-inflammatory gene expression, in vivo liver fibrosis resolution model, Yoda1 pharmacology\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with in vivo phenotype, phagolysosomal functional assay, stiffness-dependent efferocytosis established; single lab\",\n      \"pmids\": [\"38838160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Piezo1 in podocytes triggers a signaling loop involving NFATc1 and TRPC6, leading to increased calcium influx and perpetuating podocyte injury in diabetic kidney disease. TRPC6 overexpression in podocyte-specific Piezo1 knockout mice counteracted the protective effects of Piezo1 deletion, confirming the Piezo1/NFATc1/TRPC6 axis.\",\n      \"method\": \"Podocyte-specific Piezo1 conditional knockout mice, DKD model (STZ+HFD), in vitro calcium influx assays, NFATc1 and TRPC6 expression analysis, AAV-mediated TRPC6 overexpression rescue experiment\",\n      \"journal\": \"JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with rescue experiment (TRPC6 overexpression), in vivo DKD model, defined NFATc1/TRPC6 downstream pathway; single lab\",\n      \"pmids\": [\"39932793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Piezo1 in pulmonary myofibroblasts (periostin+ cells) mediates mechanosensation essential for myofibroblast activation and lung fibrosis. Loss of Piezo1 in periostin+ cells disrupts actin organization and prevents Yap/Taz nuclear localization, shifting myofibroblasts from a proliferative to an apoptotic state. Myofibroblast-specific Yap/Taz deletion fully recapitulates protective Piezo1-KO phenotypes.\",\n      \"method\": \"Postn-specific conditional Piezo1 knockout mice, actin organization imaging, Yap/Taz nuclear localization assays, myofibroblast-specific Yap/Taz knockout for epistasis, bleomycin pulmonary fibrosis model\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout in specific cell type, epistasis experiment (Yap/Taz KO recapitulates Piezo1 KO), defined actin→Yap/Taz nuclear pathway, in vivo disease model\",\n      \"pmids\": [\"40454481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PIEZO1 in vascular smooth muscle cells attenuates Marfan syndrome aortic aneurysm by inhibiting the TGF-β signaling pathway through promoting endocytosis and autophagy of TGF-β receptor 2 (TGFBR2) via Rab GTPase 3C. Smooth muscle cell-specific Piezo1 knockout exacerbates aneurysm and TGF-β pathway activation; Yoda1 activation reverses aneurysm development.\",\n      \"method\": \"VSMC-specific conditional Piezo1 knockout in MFS mice, TGFBR2 endocytosis and autophagy assays, Rab3C involvement, Yoda1 pharmacological treatment in vivo, TGF-β pathway signaling assays\",\n      \"journal\": \"European Heart Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional VSMC-specific knockout with in vivo aortic phenotype, TGFBR2 endocytosis/autophagy mechanistic dissection via Rab3C; single lab\",\n      \"pmids\": [\"39585648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Piezo1 in cardiomyocytes is elevated in diabetic cardiomyopathy and promotes mitochondrial fission via calpain activation and Drp1 dephosphorylation. Cardiac-specific Piezo1 knockout restores ERK1/2-mediated Drp1 phosphorylation (inhibitory), preserves mitochondrial dynamics, and ameliorates diabetic cardiac dysfunction and fibrosis.\",\n      \"method\": \"Cardiac-specific conditional Piezo1 knockout mice (STZ and HFD+STZ models), echocardiography, calpain activity assays, Drp1/ERK phosphorylation western blots, mitochondrial morphology and respiration assays, H9C2 cells and neonatal cardiomyocytes\",\n      \"journal\": \"Cardiovascular Diabetology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with in vivo cardiac phenotype, defined calpain/Drp1/ERK mechanistic pathway, multiple mitochondrial readouts; single lab\",\n      \"pmids\": [\"40114130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Piezo1 activation stimulates mitochondrial calcium uptake and oxidative phosphorylation (OXPHOS). Loss of Piezo1 reduces mitochondrial oxygen consumption rate and ATP production in calvarial cells, associated with increased phosphodiesterase Pde4a expression and lower cAMP levels. cAMP signaling via PKA is required for the Piezo1-induced increase in mitochondrial OXPHOS.\",\n      \"method\": \"Piezo1 conditional knockout and agonist treatment in calvarial cells, Seahorse OCR measurements, cAMP reporter assays, phosphodiesterase inhibition, PKA inhibition, mitochondrial calcium imaging\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway components tested (cAMP, PKA, phosphodiesterase), defined signaling mechanism, Seahorse metabolic measurements; single lab\",\n      \"pmids\": [\"36052712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Piezo1 in lymphatic endothelial cells acts as the upstream mechanosensor for flow-induced Orai1-KLF2-Notch lymphatic mechanotransduction pathway. Piezo1 knockdown blocks laminar flow-induced calcium influx and Orai1 downstream gene regulation; Piezo1 stimulation activates Orai1 signaling without fluid flow; Orai1 inhibition blocks Piezo1-mediated mechanotransduction, establishing Piezo1 epistatic to Orai1.\",\n      \"method\": \"Lymphatic endothelial cell Piezo1 knockdown, flow-induced calcium imaging, lymphatic-specific conditional Piezo1 knockout mice, Orai1 inhibition for epistasis, in vivo lymphatic regeneration model, Yoda1 pharmacology for lymphedema treatment\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — formal epistasis (Orai1 inhibition blocks Piezo1 effect), conditional knockout phenocopies downstream pathway knockouts, in vivo therapeutic validation; multiple orthogonal methods\",\n      \"pmids\": [\"35701867\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIEZO1 is a large homotrimeric mechanosensitive cation channel that senses membrane tension, curvature, and mechanical deformation through its curved blade-beam-pore architecture, undergoing tension-driven flattening (~300 nm² area expansion) to gate a calcium-permeable conductance; downstream calcium influx activates cell-type-specific cascades including the Gardos channel (erythrocyte volume), KCa3.1/TMEM16F (RBC PS exposure), calpain/talin/integrin β1 (adhesion and fibrosis), ERK/cyclin B (cell division), Src-p38-EGFR (regenerative signaling), cAMP/PKA (mitochondrial OXPHOS), CaMKII/YAP (mechanotransduction in bone, cartilage, and vascular cells), NFATc1/TRPC6 (podocyte injury), GRHL3/RNF114/F-actin (T cell cytotoxicity), and ATP-P2 purinergic paracrine signaling, while its gating is modulated by lipid composition (fatty acids, cholesterol), the agonist Yoda1, and the gating-modifier peptide GsMTx4, and its activity is regulated by direct protein interactions with PECAM1 and CDH5 at endothelial junctions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIEZO1 is a pore-forming, mechanically activated, calcium-permeable cation channel that transduces membrane tension and mechanical deformation into cellular calcium signals across diverse tissues [#0]. Its gating is intrinsic to the protein and to its lipid environment: cryo-EM in liposomes shows the channel adopts a curved resting state that flattens (~300 nm² in-plane area expansion) under membrane tension to open the conduction pathway, with a calculated half-maximal gating tension (~1.9 pN/nm) matching experiment [#15], and single-molecule imaging in live cells confirms that the blades are bent by resting membrane stress and expand upon activation [#23]. Membrane mechanics tune sensitivity directly — saturating versus polyunsaturated fatty acids modulate activation and inactivation by altering bilayer bending stiffness [#8] — while the synthetic agonist Yoda1 activates purified channels reconstituted in lipid bilayers and the peptide GsMTx4 inhibits gating as a membrane-mediated modifier [#5, #1]. At the cellular level, PIEZO1 couples mechanical input to calcium-dependent effectors that are interpreted in a cell-type-specific manner: in erythrocytes stretch-driven calcium influx engages the KCa3.1 Gardos channel to control cell volume and TMEM16F to drive phosphatidylserine exposure [#6, #31]; in fibroblasts, tubular, and myeloid cells calcium activates calpain-mediated talin cleavage, integrin β1, and YAP/TAZ signaling to drive adhesion, fibrosis, and macrophage polarization [#21, #38, #20]; and in endothelial and lymphatic cells shear stress activates PIEZO1 to control junction formation, leukocyte diapedesis, and the Orai1–KLF2–Notch and ANGPT2/TIE1 mechanotransduction networks [#18, #19, #42, #26]. PIEZO1 also acts as a chemo-mechanosensor — sensing microbial single-stranded RNA in gut enterochromaffin cells to govern serotonin output [#13] — and broadly couples mechanical stimulation to paracrine release of ATP, FGF1, and other ligands [#11, #12, #17]. Gain-of-function mutations in PIEZO1 cause hereditary xerocytosis, a dominant hemolytic anemia with erythrocyte dehydration [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the molecular identity of a long-sought mechanically activated cation channel, answering whether a single gene product could constitute a mechanosensor.\",\n      \"evidence\": \"RNAi knockdown and overexpression with patch-clamp electrophysiology in neuroblastoma and HEK293 cells\",\n      \"pmids\": [\"20813920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the channel's oligomeric state or structural basis of gating\", \"Endogenous physiological force inputs not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Proposed an early intracellular role linking Fam38A/Piezo1 to integrin activation via an ER-localized R-Ras/calpain/talin cascade, distinct from later plasma-membrane mechanosensing.\",\n      \"evidence\": \"siRNA knockdown, subcellular fractionation, co-IP, and pharmacological epistasis in adherent cells\",\n      \"pmids\": [\"20016066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ER localization is hard to reconcile with later plasma-membrane channel function\", \"Whether calcium release was from ER stores versus extracellular influx not definitively resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Characterized GsMTx4 as a membrane-mediated gating modifier, providing a pharmacological tool and evidence that gating is sensitive to bilayer mechanics rather than a stereospecific binding pocket.\",\n      \"evidence\": \"Patch-clamp with pressure-gating curves, enantiomer controls, and kinetic analysis in Piezo1-expressing HEK293 cells\",\n      \"pmids\": [\"21696149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular site of action on the channel/membrane not mapped\", \"Selectivity versus other mechanosensitive channels limited\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked PIEZO1 to human disease, showing gain-of-function mutations cause hereditary xerocytosis and confirming PIEZO1 is an endogenous erythrocyte membrane protein.\",\n      \"evidence\": \"Linkage, exome sequencing, segregation in kindreds, and erythrocyte membrane proteomics\",\n      \"pmids\": [\"22529292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the downstream effector linking channel hyperactivity to dehydration\", \"Mutation effects on gating biophysics not yet measured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined PIEZO1 as the endothelial shear-stress sensor required for vascular development and flow-induced cytoskeletal remodeling.\",\n      \"evidence\": \"Endothelial-specific conditional knockout mice with shear stress, cell orientation, and stress fiber assays\",\n      \"pmids\": [\"24958852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from calcium influx to cytoskeletal reorganization not detailed\", \"Embryonic lethality limited adult vascular analysis\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided a synthetic agonist (Yoda1) acting directly on purified channels and resolved the erythrocyte volume-control pathway downstream of PIEZO1.\",\n      \"evidence\": \"Compound screening with bilayer reconstitution of purified Piezo1; RBC-specific knockout with calcium imaging and Gardos channel pharmacology\",\n      \"pmids\": [\"26001275\", \"26001274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yoda1 binding site and activation mechanism not structurally defined in 2015\", \"Direct coupling between PIEZO1 calcium and Gardos channel not molecularly mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected mechanical stretch to cell-cycle progression, showing PIEZO1 drives calcium-ERK-cyclin B signaling and changes localization with cell density.\",\n      \"evidence\": \"Epithelial stretch, calcium imaging, phospho-ERK and cyclin B assays, knockdown, and live-cell PIEZO1 imaging\",\n      \"pmids\": [\"28199303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of density-dependent cytoplasmic aggregation unresolved\", \"Link between calcium and ERK activation not molecularly defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established PIEZO1 as a tunable sensor whose set-point is controlled by membrane lipid composition, with therapeutic implications for gain-of-function disease.\",\n      \"evidence\": \"Lipid profiling, electrophysiology, AFM membrane stiffness measurement, and fatty acid rescue of GOF mutant phenotypes\",\n      \"pmids\": [\"30867417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether dietary modulation translates to patients not addressed\", \"Distinct lipid effects on activation versus inactivation not fully separated mechanistically\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined PIEZO1 as the osteogenic mechanosensor coupling mechanical loading to bone formation, and demonstrated pharmacological gain-of-function increases bone mass.\",\n      \"evidence\": \"Osteoblast/osteocyte-specific conditional knockouts, fluid shear assays, microgravity simulation, and in vivo Yoda1 administration\",\n      \"pmids\": [\"31290742\", \"31588901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional program in bone cells not fully resolved here\", \"Relative contributions of osteoblasts versus osteocytes not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed PIEZO1 couples mechanosensing to paracrine ligand release, driving FGF1-dependent adipogenesis and microbial ssRNA-dependent serotonin production in the gut.\",\n      \"evidence\": \"Adipocyte- and intestinal-epithelium-specific conditional knockouts, FGF1/FGFR1 dissection, ssRNA ligand identification, and RNase A infusion\",\n      \"pmids\": [\"32385276\", \"32640190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PIEZO1 detects ssRNA chemically versus mechanically not resolved\", \"Generalizability of ligand-release coupling across tissues unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated PIEZO1 in macrophage-mediated erythrocyte turnover and systemic iron metabolism via hepcidin control, with a common human GOF allele influencing plasma iron.\",\n      \"evidence\": \"Constitutive and macrophage-specific GOF knock-in mice with hepcidin and iron assays plus human genetic association\",\n      \"pmids\": [\"33571427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking macrophage PIEZO1 activity to hepcidin not fully resolved\", \"Causal mechanical input to macrophage PIEZO1 in vivo undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the structural basis of gating, showing tension-driven flattening of the curved channel quantitatively accounts for activation tension.\",\n      \"evidence\": \"Cryo-EM of PIEZO1 in liposomes capturing curved and flattened states with in-plane area and stiffness calculations\",\n      \"pmids\": [\"35388220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational pathway between states not kinetically resolved\", \"Lipid and modifier binding sites not mapped in the structures\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the molecular machinery directing PIEZO1 to endothelial junctions, identifying PECAM1 and shear-responsive CDH5 as direct partners while excluding VEGFR2.\",\n      \"evidence\": \"Native-tagged PIEZO1 mice, reconstitution, reciprocal co-IP, high-resolution colocalization, and shear stress assays\",\n      \"pmids\": [\"37005489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of junctional targeting for channel gating not fully defined\", \"Stoichiometry of PIEZO1-PECAM1/CDH5 complexes unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded PIEZO1's vascular and inflammatory repertoire, defining its role in leukocyte diapedesis, capillary mechanosensing, lymphatic mechanotransduction, and mitochondrial OXPHOS.\",\n      \"evidence\": \"Endothelial/lymphatic conditional knockouts, capillary electrophysiology, Orai1 epistasis, phospho-signaling cascades, and Seahorse metabolic assays\",\n      \"pmids\": [\"35443048\", \"35382561\", \"35701867\", \"36052712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Multiple parallel downstream cascades not integrated into a single regulatory logic\", \"Tissue-specific determinants of which effector is engaged unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed that PIEZO1 blades are more expanded at rest in native membranes than predicted, refining the relationship between blade conformation and channel state in living cells.\",\n      \"evidence\": \"Single-molecule nanoscopic fluorescence imaging of endogenously tagged PIEZO1 with chemical and mechanical modulators\",\n      \"pmids\": [\"37587339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative link between blade expansion and open probability not established\", \"Native-cell forces shaping resting curvature not measured directly\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined quantitative biophysical gating thresholds in chondrocytes and established membrane stretch as the proximate gating stimulus.\",\n      \"evidence\": \"Single-cell AFM compression with finite element modeling, calcium imaging, and PIEZO1/2 knockout\",\n      \"pmids\": [\"37459546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Translation of stretch ratio threshold to physiological joint loading unclear\", \"Contribution of PIEZO2 versus PIEZO1 at lower strains not fully separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected PIEZO1 to immune effector mechanics and named downstream signaling networks, including neutrophil NOX4 bactericidal activity, NETosis, EGFR-ERK activation, and lymphatic ANGPT2/TIE1 signaling.\",\n      \"evidence\": \"PMN-, neutrophil-, and lymphatic-targeted manipulation with intravital imaging, microfluidics, phospho-site analysis, and conditional knockouts\",\n      \"pmids\": [\"38091995\", \"39174529\", \"37756411\", \"38747287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these cascades share a common proximal calcium-effector module is unresolved\", \"Some signaling links derive from single-lab pharmacology\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified TMEM16F as the PIEZO1-coupled phosphatidylserine scramblase in erythrocytes and defined PIEZO1 roles in adaptive and innate immune effector programs.\",\n      \"evidence\": \"Calcium/PS exposure assays in normal and HX RBCs, traction force microscopy in T cells, and ILC2/macrophage conditional knockouts\",\n      \"pmids\": [\"38033286\", \"38514773\", \"38530239\", \"38838160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical coupling between PIEZO1 and TMEM16F not structurally defined\", \"Cell-type determinants selecting GRHL3/RNF114 versus KLF2 versus YAP outputs unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended PIEZO1 into fibrotic, metabolic, and aneurysmal disease, dissecting YAP/TAZ-dependent myofibroblast activation, calpain/Drp1 mitochondrial fission, and TGFBR2 trafficking via Rab3C.\",\n      \"evidence\": \"Cell-type-specific conditional knockouts with epistasis (Yap/Taz KO), TGFBR2 endocytosis/autophagy assays, and Yoda1 in vivo treatment\",\n      \"pmids\": [\"40454481\", \"40114130\", \"39585648\", \"39932793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most disease mechanisms rest on single-lab studies\", \"How a single channel selects opposing pro- versus anti-fibrotic outputs across cell types unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying logic by which a single tension sensor is interpreted into divergent, sometimes opposing, cell-type-specific transcriptional and metabolic programs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No general model links calcium amplitude/kinetics to choice of downstream effector (Gardos, calpain, YAP, ERK, etc.)\", \"Direct partners beyond PECAM1/CDH5 that route output are largely unmapped\", \"Structural basis of chemical ligand (ssRNA) versus mechanical sensing not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 5, 6, 25, 28]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 15, 23, 25]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7, 15, 18, 23]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 19, 24, 42]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 19, 27, 32, 34]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 9, 10, 12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [16, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PECAM1\", \"CDH5\", \"TMEM16F\", \"KCNN4\", \"ORAI1\", \"TRPC6\", \"RRAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}