{"gene":"FSTL1","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2006,"finding":"MyoD directly activates transcription of miR-206, which targets sequences in the Fstl1 3' UTR and suppresses Fstl1 expression during skeletal muscle differentiation of fibroblasts converted by MyoD.","method":"miRNA target site reporter assay, MyoD-driven fibroblast-to-muscle conversion, Northern blot","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional assays with defined target sequences, replicated in multiple cell contexts","pmids":["17030984"],"is_preprint":false},{"year":2011,"finding":"Fstl1 directly binds BMP4 and negatively regulates BMP4/Smad1/5/8 signaling; genetic rescue with the BMP antagonist Noggin rescues pulmonary atelectasis in Fstl1-deficient mice, placing Fstl1 upstream of BMP4 signaling in lung development.","method":"Fstl1 knockout mouse, co-immunoprecipitation of Fstl1 with BMP4, Noggin epistasis rescue, pSmad1/5/8 signaling readout in vivo and in vitro","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo genetic epistasis with biochemical binding confirmation and multiple functional readouts in one study","pmids":["21482757"],"is_preprint":false},{"year":2013,"finding":"TGF-β signaling downregulates KSRP, switching a shared transcript from producing miR-198 to producing FSTL1 protein; FSTL1 promotes keratinocyte migration during wound re-epithelialization, while miR-198 inhibits migration by targeting DIAPH1, PLAU, and LAMC2.","method":"Human ex vivo skin organ culture, TGF-β pathway manipulation, KSRP knockdown, luciferase reporter, migration assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods in human tissue and cell systems, mechanistic pathway validated","pmids":["23395958"],"is_preprint":false},{"year":2010,"finding":"DIP2A was identified as a novel FSTL1-binding receptor on the cell surface of endothelial cells; DIP2A knockdown reduced FSTL1 binding to cells, abrogated FSTL1-stimulated survival, migration, network formation, and Akt phosphorylation in endothelial cells, and reduced FSTL1 cardioprotection in cardiac myocytes.","method":"Membrane fraction pull-down from endothelial cells, co-immunoprecipitation, siRNA knockdown of DIP2A, cell surface binding assay, functional endothelial and cardiomyocyte assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus multiple functional rescue experiments identifying receptor-mediated signaling","pmids":["20054002"],"is_preprint":false},{"year":2017,"finding":"FSTL1 promotes EMT and airway remodeling by activating autophagy; inhibition of autophagy by LY-294002 or siRNA-ATG5 reduced FSTL1-induced EMT markers (E-cadherin, N-cadherin, vimentin) in bronchial epithelial cells.","method":"OVA-challenged mouse model, Fstl1 heterozygous mice, siRNA-ATG5 and pharmacological autophagy inhibition, TEM for autophagosomes, Western blot","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro loss-of-function with defined pathway readout, single lab","pmids":["28473327"],"is_preprint":false},{"year":2017,"finding":"EGF sustains FSTL1 translation while suppressing miR-198, driving metastasis through dual pathways: FSTL1 blocks Wnt7a-mediated repression of ERK phosphorylation enabling MMP9 production; simultaneously, DIAPH1 (miR-198 target) sequesters Arpin to enhance directional migration via Arp2/3.","method":"HNSCC cell lines, luciferase reporter, FSTL1/DIAPH1 knockdown, ERK phosphorylation assay, MMP9 secretion, Arpin interaction","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway dissection with multiple functional assays, single lab","pmids":["28827448"],"is_preprint":false},{"year":2018,"finding":"Fstl1 binds DIP2A to block its nuclear translocation, preventing DIP2A from forming a complex with HDAC2-DMAP1; this increases H3K9 acetylation at the MGMT promoter and upregulates MGMT transcription, causing temozolomide resistance in glioblastoma.","method":"Co-immunoprecipitation of Fstl1 with DIP2A, chromatin immunoprecipitation (H3K9Ac at MGMT promoter), DIP2A knockdown epistasis, subcellular fractionation, in vivo xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods (Co-IP, ChIP, fractionation, epistasis) in single rigorous study","pmids":["30542120"],"is_preprint":false},{"year":2012,"finding":"Fstl1 directly binds ALK6 (BMPR1B) expressed on ureteric epithelial cells and antagonizes BMP signaling (elevated pSmad1/5/8 in Fstl1-null ureters), regulating ureteric epithelial cell proliferation and ureter development.","method":"Fstl1 knockout mouse, direct binding assay (Fstl1 to ALK6), pSmad1/5/8 immunostaining, histological analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO plus direct binding assay, single lab","pmids":["22485132"],"is_preprint":false},{"year":2017,"finding":"TGF-β1 regulates Fstl1 expression at both transcriptional and translational levels through the Smad3-c-Jun pathway; the Smad2/3 pathway is required (inhibition abolishes TGF-β1-induced Fstl1), and a functional c-Jun transcription factor binding site in the Fstl1 promoter was identified by luciferase reporter analysis.","method":"Luciferase reporter assay with Fstl1 promoter, pathway inhibitor screen (Smad, MAPK, Akt), mouse pulmonary fibroblasts","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — functional promoter dissection with pathway inhibitors, single lab","pmids":["28495857"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of the FK domain of murine Fstl1 was solved at high resolution, revealing that the FK domain forms a stable dimer in solution and in crystal; this domain is indispensable for Fstl1's function in TGF-β signaling transduction.","method":"X-ray crystallography, SEC-MALS for oligomeric state, FK domain deletion/mutation functional assay","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation of domain requirement","pmids":["31351024"],"is_preprint":false},{"year":2022,"finding":"FSTL1 interacts with Wnt ligands (via its EC and VWC domains) and Frizzled receptors (FZD4, via EC domain) but not LRP6 co-receptor, enhancing Wnt3a association with FZD4 and promoting Wnt/β-catenin signaling and fibrogenesis in obstructed kidneys.","method":"Co-immunoprecipitation, domain deletion mapping, Fstl1 overexpression/inhibition in vivo, TOP/FOP flash reporter, single-cell RNA-seq","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping and in vivo pathway validation, multiple orthogonal methods","pmids":["35525270"],"is_preprint":false},{"year":2022,"finding":"Macrophage-expressed FSTL1, through its FK domain, directly binds intracellular PKM2, promotes PKM2 phosphorylation and nuclear translocation, reduces PKM2 ubiquitination, enhances glycolysis, and increases M1 macrophage polarization to promote liver fibrosis.","method":"Myeloid-specific FSTL1 KO mice, Co-IP of FSTL1 with PKM2, PKM2 phosphorylation/ubiquitination assays, nuclear fractionation, pharmacological PKM2 activator rescue","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — domain-specific binding, multiple biochemical assays plus in vivo KO model, replicated across three fibrosis models","pmids":["35140065"],"is_preprint":false},{"year":2021,"finding":"FSTL1 secreted by activated fibroblasts binds TLR4 on hepatocellular carcinoma cells, activating AKT/mTOR/4EBP1 signaling to promote HCC growth, metastasis, and tumor-initiating cell maintenance.","method":"Recombinant FSTL1 treatment, FSTL1 overexpression conditioned medium, TLR4 binding assay, AKT/mTOR pathway readout, patient-derived 3D organoids, preclinical mouse model with FSTL1 blockade","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — receptor binding with downstream pathway validation and in vivo rescue, single lab","pmids":["34551961"],"is_preprint":false},{"year":2020,"finding":"Dynamic resistance exercise stimulates skeletal muscle FSTL1 secretion; FSTL1 binds DIP2A receptor on endothelial cells and activates Smad2/3 signaling (independent of TGFβR1) to induce VEGF-A expression and promote cardiac angiogenesis post-myocardial infarction.","method":"AAV-FSTL1 injection, TGFβR1 inhibitor, DIP2A immunofluorescence, pSmad2/3 Western blot, HUVEC tube formation assay, rat MI model","journal":"Journal of sport and health science","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro pathway dissection showing DIP2A-Smad2/3 independence from TGFβR1, single lab","pmids":["33246164"],"is_preprint":false},{"year":2017,"finding":"Fstl1 competitively binds BMP4 but not BMPR2, inhibiting BMP4-BMPR2 association and suppressing BMP4/Smad1/5/8 pathway activation, thereby promoting glioma cell proliferation.","method":"Co-immunoprecipitation of Fstl1 with BMP4 and BMPR2, BMP4 overexpression rescue, pSmad1/5/8 readout, orthotopic xenograft","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP-based binding competition with genetic epistasis, single lab","pmids":["29212066"],"is_preprint":false},{"year":2018,"finding":"FSTL1 promotes CRC metastasis through activation of focal adhesion signaling and cytoskeleton rearrangement; FSTL1 interacts with VIM (vimentin) as identified by co-immunoprecipitation, and TGFβ1 induces FSTL1 expression via Smad3 transcription factor.","method":"Co-immunoprecipitation of FSTL1 with VIM, Smad3 transcription factor reporter, FSTL1 knockdown/overexpression migration/invasion assays, focal adhesion pathway readout","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP binding partner identified with pathway readout and upstream transcriptional regulation, single lab","pmids":["29844309"],"is_preprint":false},{"year":2017,"finding":"FSTL1 promotes ESCC oncogenesis via NFκB-BMP signaling cross-talk; functional rescue experiments with NFκB and TLR4 inhibitors established pathway interdependence.","method":"FSTL1 shRNA and neutralizing antibody, mRNA profiling, NFκB/TLR4 inhibitor functional rescue, in vivo metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function plus pathway inhibitor rescue, single lab","pmids":["28883005"],"is_preprint":false},{"year":2017,"finding":"Deletion of Fstl1 from the endocardial/endothelial lineage (Tie2-Cre) leads to sustained BMP and TGFβ signaling, ongoing EndMT and proliferation, causing myxomatous mitral valve disease, heart failure, and death, establishing Fstl1 as a negative regulator of BMP/TGFβ signaling in the endocardium.","method":"Conditional Tie2-Cre knockout, histology, echocardiography, BMP/TGFβ pathway immunostaining","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined molecular pathway readout, single lab","pmids":["28705792"],"is_preprint":false},{"year":2020,"finding":"Recombinant FSTL1 treatment of macrophages attenuates NF-κB p65 phosphorylation in an Nr4a1-dependent manner, placing Fstl1 upstream of Nr4a1-mediated NF-κB suppression in lung macrophages; FSTL1 hypomorphic mice develop spontaneous emphysema with dysregulated Nr4a1 expression.","method":"RNA sequencing, recombinant FSTL1 macrophage treatment, Nr4a1-dependent NF-κB p65 phosphorylation assay, FSTL1 hypomorphic mouse lung morphometry","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro mechanistic pathway dissection confirmed in hypomorphic mouse model, single lab","pmids":["31834999"],"is_preprint":false},{"year":2023,"finding":"Skeletal muscle IRF4 transcriptionally regulates FSTL1 (confirmed by dual-luciferase assay); muscle-secreted FSTL1 acts on liver cells via distinct receptors (DIP2A and CD14) in different liver cell types to promote NASH pathology.","method":"Muscle-specific IRF4 KO mice, dual-luciferase reporter for FSTL1 promoter, proteomics, muscle FSTL1 re-expression rescue, co-culture experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis, transcriptional reporter, and receptor assignment with multiple cell-type-specific readouts in vivo and in vitro","pmids":["37770480"],"is_preprint":false},{"year":2017,"finding":"Fstl1 deletion in mice causes loss of myocardin/SRF transcription factors and impaired differentiation of airway smooth muscle cells, establishing Fstl1 as a regulator of smooth muscle cell differentiation in lung airway development.","method":"Fstl1 knockout mice, lacZ reporter for expression localization, histology, myocardin/SRF Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with defined molecular mechanism (myocardin/SRF), single lab","pmids":["28574994"],"is_preprint":false},{"year":2020,"finding":"FSTL1 promotes chondrocyte apoptosis via activation of the SAPK/JNK/Caspase3 signaling pathway; caspase-3 inhibitor Ac-DEVD-FMK impaired FSTL1-induced apoptosis.","method":"FSTL1 overexpression in human chondrocytes, flow cytometry apoptosis assay, Western blot for SAPK/JNK/Caspase3, pharmacological inhibitor rescue","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — pathway-specific inhibitor rescue with biochemical confirmation, single lab","pmids":["31927008"],"is_preprint":false},{"year":2023,"finding":"H2S stabilizes FSTL1 transcript via HuR (RNA-binding protein); FSTL1 activates Src kinase to open endothelial intercellular junctions (decreasing VE-cadherin, occludin, claudin-5, connexin-43), initiating angiogenesis independently of VEGFR2.","method":"siRNA knockdown of HuR, Src inhibitor vs. VEGFR2 inhibitor comparison, immunostaining of junction proteins, HUVEC permeability assay, hindlimb ischemia mouse model","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — pathway delineation with inhibitor specificity and mechanistic readouts, single lab","pmids":["37694287"],"is_preprint":false},{"year":2023,"finding":"FSTL1 promotes alveolar epithelial cell senescence through TGF-β1 signaling in a SENP1-dependent manner; FSTL1 upregulates SENP1 expression, and SENP1 mediates deSUMOylation of Smad4 and Ras to enhance TGF-β pathway activation; SENP1 knockdown blocked FSTL1-enhanced senescence and pulmonary fibrosis.","method":"FSTL1 overexpression in AECs, SENP1 siRNA knockdown, TGF-β signaling pathway assay, mouse pulmonary fibrosis model","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via SENP1 knockdown with defined molecular mechanism, single lab","pmids":["37369969"],"is_preprint":false}],"current_model":"FSTL1 is a secreted, multifunctional glycoprotein that antagonizes BMP signaling by directly binding BMP4 (and ALK6), promotes TGF-β/Smad2/3 signaling (regulated transcriptionally via Smad3-c-Jun), mediates cellular effects through the DIP2A receptor (activating Smad2/3 and Akt) and TLR4 receptor (activating NF-κB/AKT/mTOR), interacts intracellularly with PKM2 (via its FK domain) to reprogram macrophage glycolysis and M1 polarization, competes with BMPR2 for BMP4 binding to modulate glioma growth, enhances Wnt/β-catenin signaling by bridging Wnt ligands to Frizzled receptors, and is post-transcriptionally regulated by a TGF-β/KSRP-controlled switch that determines whether its shared transcript produces miR-198 or FSTL1 protein."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing that FSTL1 is subject to post-transcriptional regulation by tissue-specific miRNAs revealed it as a dynamically controlled gene rather than a constitutively expressed factor.","evidence":"miR-206 target site reporter assay and MyoD-driven fibroblast-to-muscle conversion showing miR-206 suppresses Fstl1 during skeletal muscle differentiation","pmids":["17030984"],"confidence":"High","gaps":["Whether miR-206 regulation of FSTL1 operates in vivo during myogenesis was not tested","Other miRNAs targeting FSTL1 were not surveyed"]},{"year":2010,"claim":"Identification of DIP2A as a cell-surface receptor for FSTL1 established a direct signaling mechanism through which secreted FSTL1 activates Akt to promote endothelial survival and cardioprotection.","evidence":"Membrane fraction pull-down, reciprocal Co-IP, DIP2A siRNA ablation of FSTL1 binding and downstream Akt phosphorylation in endothelial cells and cardiomyocytes","pmids":["20054002"],"confidence":"High","gaps":["Structural basis of FSTL1-DIP2A interaction unknown","Whether DIP2A mediates all FSTL1 functions or only a subset was unresolved"]},{"year":2011,"claim":"Demonstrating that FSTL1 directly binds BMP4 and functionally antagonizes BMP/Smad1/5/8 signaling in vivo resolved FSTL1's mechanism as a secreted BMP antagonist essential for lung morphogenesis.","evidence":"Fstl1 knockout mouse with pulmonary atelectasis, Co-IP of Fstl1 with BMP4, Noggin epistasis rescue restoring lung development","pmids":["21482757"],"confidence":"High","gaps":["Relative affinities of FSTL1 for different BMP family ligands not determined","Whether FSTL1 antagonism is stoichiometric or catalytic was unclear"]},{"year":2012,"claim":"Showing that FSTL1 also directly binds the BMP type I receptor ALK6 expanded the antagonism mechanism beyond ligand sequestration to receptor-level inhibition.","evidence":"Direct binding assay of Fstl1 to ALK6, elevated pSmad1/5/8 in Fstl1-null ureters, Fstl1 knockout mouse ureter phenotype","pmids":["22485132"],"confidence":"Medium","gaps":["Whether FSTL1 blocks BMP-ALK6 association or alters receptor conformation was not distinguished","Binding affinity not quantified"]},{"year":2013,"claim":"Discovery of the TGF-β/KSRP-controlled molecular switch between miR-198 and FSTL1 protein from a shared transcript revealed an elegant post-transcriptional mechanism coupling wound healing signals to FSTL1 production.","evidence":"Human ex vivo skin organ culture, KSRP knockdown toggling miR-198/FSTL1 output, TGF-β pathway manipulation, migration assays","pmids":["23395958"],"confidence":"High","gaps":["Whether this switch operates in tissues beyond skin was not tested","Quantitative kinetics of the switch in vivo unknown"]},{"year":2017,"claim":"A cluster of studies in 2017 expanded FSTL1's downstream signaling repertoire to include TLR4/NF-κB, autophagy/EMT, Smad3-c-Jun transcriptional regulation of Fstl1 itself, smooth muscle differentiation via myocardin/SRF, and competitive BMP4 sequestration from BMPR2 in glioma, revealing FSTL1 as a pleiotropic factor operating through multiple receptor-pathway axes in different tissues.","evidence":"Conditional Tie2-Cre KO (endocardium), OVA-challenged Fstl1 heterozygous mice (autophagy/EMT), Fstl1 promoter luciferase reporter (Smad3-c-Jun), BMP4-BMPR2 competition Co-IP (glioma), NF-κB/TLR4 inhibitor rescue (ESCC), myocardin/SRF loss in Fstl1 KO lungs","pmids":["28705792","28473327","28495857","29212066","28883005","28574994","28827448"],"confidence":"Medium","gaps":["Which receptor (DIP2A, TLR4, or others) mediates each tissue-specific effect not systematically resolved","Relative contributions of BMP antagonism vs. TLR4 signaling in the same tissue not compared","EGF-FSTL1-Wnt7a axis replicated only in HNSCC cells"]},{"year":2018,"claim":"Demonstrating that FSTL1 sequesters DIP2A at the cell surface to prevent its nuclear HDAC2 complex formation revealed a non-canonical receptor-blocking mechanism linking FSTL1 to epigenetic regulation of chemoresistance.","evidence":"Co-IP of Fstl1 with DIP2A, subcellular fractionation, ChIP showing increased H3K9Ac at MGMT promoter upon FSTL1 exposure, DIP2A knockdown epistasis, glioblastoma xenograft","pmids":["30542120"],"confidence":"High","gaps":["Whether this DIP2A sequestration mechanism operates at other loci beyond MGMT not tested","Structural basis of cytoplasmic DIP2A retention by FSTL1 undefined"]},{"year":2019,"claim":"The crystal structure of the FK domain revealed a stable dimer and established this domain as structurally and functionally indispensable for TGF-β signaling, providing the first structural framework for FSTL1 function.","evidence":"X-ray crystallography of murine Fstl1 FK domain, SEC-MALS confirming dimerization, FK domain deletion abolishing TGF-β signaling","pmids":["31351024"],"confidence":"High","gaps":["Full-length FSTL1 structure not solved","Whether dimerization is required for receptor engagement unknown","Structure of FSTL1 in complex with any binding partner not available"]},{"year":2020,"claim":"Two studies refined FSTL1's immunomodulatory and angiogenic roles: FSTL1 suppresses NF-κB via Nr4a1 in lung macrophages, and FSTL1 signals through DIP2A-Smad2/3 independently of TGFβR1 to drive cardiac angiogenesis.","evidence":"Recombinant FSTL1 macrophage treatment with Nr4a1-dependent NF-κB readout, FSTL1 hypomorphic mice with emphysema; AAV-FSTL1 in rat MI model with TGFβR1 inhibitor demonstrating DIP2A-Smad2/3 independence","pmids":["31834999","33246164"],"confidence":"Medium","gaps":["Direct Nr4a1-FSTL1 binding not demonstrated","Whether DIP2A-Smad2/3 and DIP2A-Akt are activated simultaneously or context-dependently not resolved"]},{"year":2022,"claim":"Two discoveries in 2022 substantially expanded FSTL1's mechanism: its EC and VWC domains bridge Wnt ligands to Frizzled receptors to enhance Wnt/β-catenin signaling, and its FK domain binds intracellular PKM2 to reprogram macrophage glycolysis and drive M1 polarization, the latter representing the first intracellular signaling function of FSTL1.","evidence":"Domain deletion Co-IP mapping FSTL1-Wnt-FZD4 interactions, TOP/FOP reporter (kidney fibrosis model); myeloid-specific FSTL1 KO mice, FSTL1-PKM2 Co-IP, PKM2 phosphorylation/ubiquitination assays across three liver fibrosis models","pmids":["35525270","35140065"],"confidence":"High","gaps":["How secreted FSTL1 accesses intracellular PKM2 in macrophages not mechanistically explained","Whether Wnt potentiation and BMP antagonism occur simultaneously in the same cell unclear","Whether FSTL1-PKM2 interaction occurs in cell types beyond macrophages not tested"]},{"year":2023,"claim":"Recent work expanded FSTL1's transcriptional regulation (IRF4 in muscle), receptor usage (CD14 as an additional liver receptor), post-transcriptional stabilization (HuR), and downstream effectors (Src kinase for junction opening; SENP1 for deSUMOylation-dependent TGF-β amplification).","evidence":"Muscle-specific IRF4 KO with FSTL1 promoter luciferase and DIP2A/CD14 receptor assignment in liver cell types; HuR siRNA and Src inhibitor in HUVECs; SENP1 knockdown blocking FSTL1-induced senescence via Smad4/Ras deSUMOylation","pmids":["37770480","37694287","37369969"],"confidence":"Medium","gaps":["CD14 as FSTL1 receptor demonstrated only in liver; generality unknown","How FSTL1 upregulates SENP1 mechanistically not defined","Whether H2S-HuR-FSTL1 axis operates outside endothelial cells not tested"]},{"year":null,"claim":"Critical open questions include: the full-length FSTL1 structure and how domain architecture determines selective receptor engagement; how secreted FSTL1 accesses intracellular PKM2; the hierarchy among DIP2A, TLR4, CD14, and Frizzled as FSTL1 receptors in different tissues; and whether FSTL1 dimerization (via FK domain) is required for specific receptor interactions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length FSTL1 structure available","Mechanism of FSTL1 intracellular access for PKM2 binding undefined","Systematic receptor selectivity across tissues not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7,10,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,12,13]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,3,10,11,12,13]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,7,17,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,16,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,12,14]}],"complexes":[],"partners":["BMP4","DIP2A","ALK6","PKM2","FZD4","TLR4","VIM"],"other_free_text":[]},"mechanistic_narrative":"FSTL1 is a secreted glycoprotein that functions as a context-dependent modulator of BMP, TGF-β, and Wnt signaling pathways, with broad roles in organogenesis, tissue repair, fibrosis, and immune regulation. Extracellularly, FSTL1 directly binds BMP4 and the BMP receptor ALK6 to antagonize BMP/Smad1/5/8 signaling in lung, ureter, and endocardial development [PMID:21482757, PMID:22485132, PMID:28705792], while it enhances Wnt/β-catenin signaling by bridging Wnt ligands to Frizzled receptors via its EC and VWC domains [PMID:35525270]. FSTL1 signals through the cell-surface receptor DIP2A to activate Smad2/3 and Akt independently of TGFβR1, mediating endothelial survival, cardiac angiogenesis, and glioblastoma chemoresistance by blocking DIP2A nuclear translocation and HDAC2-dependent MGMT silencing [PMID:20054002, PMID:33246164, PMID:30542120]; it also engages TLR4 to activate NF-κB/AKT/mTOR signaling in tumor cells [PMID:34551961, PMID:28883005]. Intracellularly in macrophages, its FK domain binds PKM2 to promote glycolytic reprogramming and M1 polarization driving liver fibrosis [PMID:35140065], and its own expression is controlled by a TGF-β/KSRP-dependent switch that toggles between miR-198 and FSTL1 protein production from a shared transcript [PMID:23395958]."},"prefetch_data":{"uniprot":{"accession":"Q12841","full_name":"Follistatin-related protein 1","aliases":["Follistatin-like protein 1"],"length_aa":308,"mass_kda":35.0,"function":"Secreted glycoprotein that is involved in various physiological processes, such as angiogenesis, regulation of the immune response, cell proliferation and differentiation (PubMed:22265692, PubMed:29212066). Plays a role in the development of the central nervous system, skeletal system, lungs, and ureter (By similarity). Promotes endothelial cell survival, migration and differentiation into network structures in an AKT-dependent manner. Also promotes survival of cardiac myocytes (By similarity). 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Pathway.","date":"2024","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/38316670","citation_count":15,"is_preprint":false},{"pmid":"34555658","id":"PMC_34555658","title":"Circ_0001490/miR-579-3p/FSTL1 axis modulates the survival of mycobacteria and the viability, apoptosis and inflammatory response in Mycobacterium tuberculosis-infected macrophages.","date":"2021","source":"Tuberculosis (Edinburgh, Scotland)","url":"https://pubmed.ncbi.nlm.nih.gov/34555658","citation_count":15,"is_preprint":false},{"pmid":"31927008","id":"PMC_31927008","title":"FSTL1 promotes nitric oxide-induced chondrocyte apoptosis via activating the SAPK/JNK/caspase3 signaling pathway.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/31927008","citation_count":15,"is_preprint":false},{"pmid":"15638044","id":"PMC_15638044","title":"Follistatin-related protein gene (FRP) is expressed in the synovial tissues of rheumatoid arthritis, but its polymorphisms are not associated with genetic susceptibility.","date":"2004","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/15638044","citation_count":15,"is_preprint":false},{"pmid":"33825599","id":"PMC_33825599","title":"The lncRNA PVT1/miR-590-5p/FSTL1 axis modulates the proliferation and migration of airway smooth muscle cells in asthma.","date":"2021","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/33825599","citation_count":15,"is_preprint":false},{"pmid":"35406177","id":"PMC_35406177","title":"Ensemble Tree-Based Approach towards Flexural Strength Prediction of FRP Reinforced Concrete Beams.","date":"2022","source":"Polymers","url":"https://pubmed.ncbi.nlm.nih.gov/35406177","citation_count":15,"is_preprint":false},{"pmid":"37369969","id":"PMC_37369969","title":"FSTL1 promotes alveolar epithelial cell aging and worsens pulmonary fibrosis by affecting SENP1-mediated DeSUMOylation.","date":"2023","source":"Cell biology 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37694287","citation_count":12,"is_preprint":false},{"pmid":"35933079","id":"PMC_35933079","title":"CircPTTG1IP knockdown suppresses rheumatoid arthritis progression by targeting miR-431-5p/FSTL1 axis.","date":"2022","source":"Transplant immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35933079","citation_count":12,"is_preprint":false},{"pmid":"33709299","id":"PMC_33709299","title":"Inhibition of microRNA-143-3p Attenuates Cerebral Ischemia/Reperfusion Injury by Targeting FSTL1.","date":"2021","source":"Neuromolecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33709299","citation_count":12,"is_preprint":false},{"pmid":"11069718","id":"PMC_11069718","title":"Induction of c-Src in human blood monocytes by anti-CD98/FRP-1 mAb in an Sp1-dependent fashion.","date":"2000","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11069718","citation_count":12,"is_preprint":false},{"pmid":"25510360","id":"PMC_25510360","title":"The role of oxidation in FSL-1 induced signaling pathways of an atopic dermatitis model in HaCaT keratinocytes.","date":"2015","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/25510360","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53770,"output_tokens":5767,"usd":0.123908},"stage2":{"model":"claude-opus-4-6","input_tokens":9433,"output_tokens":3713,"usd":0.209985},"total_usd":0.333893,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"MyoD directly activates transcription of miR-206, which targets sequences in the Fstl1 3' UTR and suppresses Fstl1 expression during skeletal muscle differentiation of fibroblasts converted by MyoD.\",\n      \"method\": \"miRNA target site reporter assay, MyoD-driven fibroblast-to-muscle conversion, Northern blot\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional assays with defined target sequences, replicated in multiple cell contexts\",\n      \"pmids\": [\"17030984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fstl1 directly binds BMP4 and negatively regulates BMP4/Smad1/5/8 signaling; genetic rescue with the BMP antagonist Noggin rescues pulmonary atelectasis in Fstl1-deficient mice, placing Fstl1 upstream of BMP4 signaling in lung development.\",\n      \"method\": \"Fstl1 knockout mouse, co-immunoprecipitation of Fstl1 with BMP4, Noggin epistasis rescue, pSmad1/5/8 signaling readout in vivo and in vitro\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo genetic epistasis with biochemical binding confirmation and multiple functional readouts in one study\",\n      \"pmids\": [\"21482757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TGF-β signaling downregulates KSRP, switching a shared transcript from producing miR-198 to producing FSTL1 protein; FSTL1 promotes keratinocyte migration during wound re-epithelialization, while miR-198 inhibits migration by targeting DIAPH1, PLAU, and LAMC2.\",\n      \"method\": \"Human ex vivo skin organ culture, TGF-β pathway manipulation, KSRP knockdown, luciferase reporter, migration assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods in human tissue and cell systems, mechanistic pathway validated\",\n      \"pmids\": [\"23395958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DIP2A was identified as a novel FSTL1-binding receptor on the cell surface of endothelial cells; DIP2A knockdown reduced FSTL1 binding to cells, abrogated FSTL1-stimulated survival, migration, network formation, and Akt phosphorylation in endothelial cells, and reduced FSTL1 cardioprotection in cardiac myocytes.\",\n      \"method\": \"Membrane fraction pull-down from endothelial cells, co-immunoprecipitation, siRNA knockdown of DIP2A, cell surface binding assay, functional endothelial and cardiomyocyte assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus multiple functional rescue experiments identifying receptor-mediated signaling\",\n      \"pmids\": [\"20054002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FSTL1 promotes EMT and airway remodeling by activating autophagy; inhibition of autophagy by LY-294002 or siRNA-ATG5 reduced FSTL1-induced EMT markers (E-cadherin, N-cadherin, vimentin) in bronchial epithelial cells.\",\n      \"method\": \"OVA-challenged mouse model, Fstl1 heterozygous mice, siRNA-ATG5 and pharmacological autophagy inhibition, TEM for autophagosomes, Western blot\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro loss-of-function with defined pathway readout, single lab\",\n      \"pmids\": [\"28473327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EGF sustains FSTL1 translation while suppressing miR-198, driving metastasis through dual pathways: FSTL1 blocks Wnt7a-mediated repression of ERK phosphorylation enabling MMP9 production; simultaneously, DIAPH1 (miR-198 target) sequesters Arpin to enhance directional migration via Arp2/3.\",\n      \"method\": \"HNSCC cell lines, luciferase reporter, FSTL1/DIAPH1 knockdown, ERK phosphorylation assay, MMP9 secretion, Arpin interaction\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with multiple functional assays, single lab\",\n      \"pmids\": [\"28827448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Fstl1 binds DIP2A to block its nuclear translocation, preventing DIP2A from forming a complex with HDAC2-DMAP1; this increases H3K9 acetylation at the MGMT promoter and upregulates MGMT transcription, causing temozolomide resistance in glioblastoma.\",\n      \"method\": \"Co-immunoprecipitation of Fstl1 with DIP2A, chromatin immunoprecipitation (H3K9Ac at MGMT promoter), DIP2A knockdown epistasis, subcellular fractionation, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods (Co-IP, ChIP, fractionation, epistasis) in single rigorous study\",\n      \"pmids\": [\"30542120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Fstl1 directly binds ALK6 (BMPR1B) expressed on ureteric epithelial cells and antagonizes BMP signaling (elevated pSmad1/5/8 in Fstl1-null ureters), regulating ureteric epithelial cell proliferation and ureter development.\",\n      \"method\": \"Fstl1 knockout mouse, direct binding assay (Fstl1 to ALK6), pSmad1/5/8 immunostaining, histological analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO plus direct binding assay, single lab\",\n      \"pmids\": [\"22485132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGF-β1 regulates Fstl1 expression at both transcriptional and translational levels through the Smad3-c-Jun pathway; the Smad2/3 pathway is required (inhibition abolishes TGF-β1-induced Fstl1), and a functional c-Jun transcription factor binding site in the Fstl1 promoter was identified by luciferase reporter analysis.\",\n      \"method\": \"Luciferase reporter assay with Fstl1 promoter, pathway inhibitor screen (Smad, MAPK, Akt), mouse pulmonary fibroblasts\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional promoter dissection with pathway inhibitors, single lab\",\n      \"pmids\": [\"28495857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of the FK domain of murine Fstl1 was solved at high resolution, revealing that the FK domain forms a stable dimer in solution and in crystal; this domain is indispensable for Fstl1's function in TGF-β signaling transduction.\",\n      \"method\": \"X-ray crystallography, SEC-MALS for oligomeric state, FK domain deletion/mutation functional assay\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation of domain requirement\",\n      \"pmids\": [\"31351024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FSTL1 interacts with Wnt ligands (via its EC and VWC domains) and Frizzled receptors (FZD4, via EC domain) but not LRP6 co-receptor, enhancing Wnt3a association with FZD4 and promoting Wnt/β-catenin signaling and fibrogenesis in obstructed kidneys.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mapping, Fstl1 overexpression/inhibition in vivo, TOP/FOP flash reporter, single-cell RNA-seq\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping and in vivo pathway validation, multiple orthogonal methods\",\n      \"pmids\": [\"35525270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Macrophage-expressed FSTL1, through its FK domain, directly binds intracellular PKM2, promotes PKM2 phosphorylation and nuclear translocation, reduces PKM2 ubiquitination, enhances glycolysis, and increases M1 macrophage polarization to promote liver fibrosis.\",\n      \"method\": \"Myeloid-specific FSTL1 KO mice, Co-IP of FSTL1 with PKM2, PKM2 phosphorylation/ubiquitination assays, nuclear fractionation, pharmacological PKM2 activator rescue\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific binding, multiple biochemical assays plus in vivo KO model, replicated across three fibrosis models\",\n      \"pmids\": [\"35140065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FSTL1 secreted by activated fibroblasts binds TLR4 on hepatocellular carcinoma cells, activating AKT/mTOR/4EBP1 signaling to promote HCC growth, metastasis, and tumor-initiating cell maintenance.\",\n      \"method\": \"Recombinant FSTL1 treatment, FSTL1 overexpression conditioned medium, TLR4 binding assay, AKT/mTOR pathway readout, patient-derived 3D organoids, preclinical mouse model with FSTL1 blockade\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor binding with downstream pathway validation and in vivo rescue, single lab\",\n      \"pmids\": [\"34551961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dynamic resistance exercise stimulates skeletal muscle FSTL1 secretion; FSTL1 binds DIP2A receptor on endothelial cells and activates Smad2/3 signaling (independent of TGFβR1) to induce VEGF-A expression and promote cardiac angiogenesis post-myocardial infarction.\",\n      \"method\": \"AAV-FSTL1 injection, TGFβR1 inhibitor, DIP2A immunofluorescence, pSmad2/3 Western blot, HUVEC tube formation assay, rat MI model\",\n      \"journal\": \"Journal of sport and health science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro pathway dissection showing DIP2A-Smad2/3 independence from TGFβR1, single lab\",\n      \"pmids\": [\"33246164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fstl1 competitively binds BMP4 but not BMPR2, inhibiting BMP4-BMPR2 association and suppressing BMP4/Smad1/5/8 pathway activation, thereby promoting glioma cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation of Fstl1 with BMP4 and BMPR2, BMP4 overexpression rescue, pSmad1/5/8 readout, orthotopic xenograft\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP-based binding competition with genetic epistasis, single lab\",\n      \"pmids\": [\"29212066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FSTL1 promotes CRC metastasis through activation of focal adhesion signaling and cytoskeleton rearrangement; FSTL1 interacts with VIM (vimentin) as identified by co-immunoprecipitation, and TGFβ1 induces FSTL1 expression via Smad3 transcription factor.\",\n      \"method\": \"Co-immunoprecipitation of FSTL1 with VIM, Smad3 transcription factor reporter, FSTL1 knockdown/overexpression migration/invasion assays, focal adhesion pathway readout\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP binding partner identified with pathway readout and upstream transcriptional regulation, single lab\",\n      \"pmids\": [\"29844309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FSTL1 promotes ESCC oncogenesis via NFκB-BMP signaling cross-talk; functional rescue experiments with NFκB and TLR4 inhibitors established pathway interdependence.\",\n      \"method\": \"FSTL1 shRNA and neutralizing antibody, mRNA profiling, NFκB/TLR4 inhibitor functional rescue, in vivo metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function plus pathway inhibitor rescue, single lab\",\n      \"pmids\": [\"28883005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Deletion of Fstl1 from the endocardial/endothelial lineage (Tie2-Cre) leads to sustained BMP and TGFβ signaling, ongoing EndMT and proliferation, causing myxomatous mitral valve disease, heart failure, and death, establishing Fstl1 as a negative regulator of BMP/TGFβ signaling in the endocardium.\",\n      \"method\": \"Conditional Tie2-Cre knockout, histology, echocardiography, BMP/TGFβ pathway immunostaining\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined molecular pathway readout, single lab\",\n      \"pmids\": [\"28705792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Recombinant FSTL1 treatment of macrophages attenuates NF-κB p65 phosphorylation in an Nr4a1-dependent manner, placing Fstl1 upstream of Nr4a1-mediated NF-κB suppression in lung macrophages; FSTL1 hypomorphic mice develop spontaneous emphysema with dysregulated Nr4a1 expression.\",\n      \"method\": \"RNA sequencing, recombinant FSTL1 macrophage treatment, Nr4a1-dependent NF-κB p65 phosphorylation assay, FSTL1 hypomorphic mouse lung morphometry\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic pathway dissection confirmed in hypomorphic mouse model, single lab\",\n      \"pmids\": [\"31834999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Skeletal muscle IRF4 transcriptionally regulates FSTL1 (confirmed by dual-luciferase assay); muscle-secreted FSTL1 acts on liver cells via distinct receptors (DIP2A and CD14) in different liver cell types to promote NASH pathology.\",\n      \"method\": \"Muscle-specific IRF4 KO mice, dual-luciferase reporter for FSTL1 promoter, proteomics, muscle FSTL1 re-expression rescue, co-culture experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis, transcriptional reporter, and receptor assignment with multiple cell-type-specific readouts in vivo and in vitro\",\n      \"pmids\": [\"37770480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fstl1 deletion in mice causes loss of myocardin/SRF transcription factors and impaired differentiation of airway smooth muscle cells, establishing Fstl1 as a regulator of smooth muscle cell differentiation in lung airway development.\",\n      \"method\": \"Fstl1 knockout mice, lacZ reporter for expression localization, histology, myocardin/SRF Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined molecular mechanism (myocardin/SRF), single lab\",\n      \"pmids\": [\"28574994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FSTL1 promotes chondrocyte apoptosis via activation of the SAPK/JNK/Caspase3 signaling pathway; caspase-3 inhibitor Ac-DEVD-FMK impaired FSTL1-induced apoptosis.\",\n      \"method\": \"FSTL1 overexpression in human chondrocytes, flow cytometry apoptosis assay, Western blot for SAPK/JNK/Caspase3, pharmacological inhibitor rescue\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway-specific inhibitor rescue with biochemical confirmation, single lab\",\n      \"pmids\": [\"31927008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"H2S stabilizes FSTL1 transcript via HuR (RNA-binding protein); FSTL1 activates Src kinase to open endothelial intercellular junctions (decreasing VE-cadherin, occludin, claudin-5, connexin-43), initiating angiogenesis independently of VEGFR2.\",\n      \"method\": \"siRNA knockdown of HuR, Src inhibitor vs. VEGFR2 inhibitor comparison, immunostaining of junction proteins, HUVEC permeability assay, hindlimb ischemia mouse model\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway delineation with inhibitor specificity and mechanistic readouts, single lab\",\n      \"pmids\": [\"37694287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FSTL1 promotes alveolar epithelial cell senescence through TGF-β1 signaling in a SENP1-dependent manner; FSTL1 upregulates SENP1 expression, and SENP1 mediates deSUMOylation of Smad4 and Ras to enhance TGF-β pathway activation; SENP1 knockdown blocked FSTL1-enhanced senescence and pulmonary fibrosis.\",\n      \"method\": \"FSTL1 overexpression in AECs, SENP1 siRNA knockdown, TGF-β signaling pathway assay, mouse pulmonary fibrosis model\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via SENP1 knockdown with defined molecular mechanism, single lab\",\n      \"pmids\": [\"37369969\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FSTL1 is a secreted, multifunctional glycoprotein that antagonizes BMP signaling by directly binding BMP4 (and ALK6), promotes TGF-β/Smad2/3 signaling (regulated transcriptionally via Smad3-c-Jun), mediates cellular effects through the DIP2A receptor (activating Smad2/3 and Akt) and TLR4 receptor (activating NF-κB/AKT/mTOR), interacts intracellularly with PKM2 (via its FK domain) to reprogram macrophage glycolysis and M1 polarization, competes with BMPR2 for BMP4 binding to modulate glioma growth, enhances Wnt/β-catenin signaling by bridging Wnt ligands to Frizzled receptors, and is post-transcriptionally regulated by a TGF-β/KSRP-controlled switch that determines whether its shared transcript produces miR-198 or FSTL1 protein.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FSTL1 is a secreted glycoprotein that functions as a context-dependent modulator of BMP, TGF-β, and Wnt signaling pathways, with broad roles in organogenesis, tissue repair, fibrosis, and immune regulation. Extracellularly, FSTL1 directly binds BMP4 and the BMP receptor ALK6 to antagonize BMP/Smad1/5/8 signaling in lung, ureter, and endocardial development [PMID:21482757, PMID:22485132, PMID:28705792], while it enhances Wnt/β-catenin signaling by bridging Wnt ligands to Frizzled receptors via its EC and VWC domains [PMID:35525270]. FSTL1 signals through the cell-surface receptor DIP2A to activate Smad2/3 and Akt independently of TGFβR1, mediating endothelial survival, cardiac angiogenesis, and glioblastoma chemoresistance by blocking DIP2A nuclear translocation and HDAC2-dependent MGMT silencing [PMID:20054002, PMID:33246164, PMID:30542120]; it also engages TLR4 to activate NF-κB/AKT/mTOR signaling in tumor cells [PMID:34551961, PMID:28883005]. Intracellularly in macrophages, its FK domain binds PKM2 to promote glycolytic reprogramming and M1 polarization driving liver fibrosis [PMID:35140065], and its own expression is controlled by a TGF-β/KSRP-dependent switch that toggles between miR-198 and FSTL1 protein production from a shared transcript [PMID:23395958].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that FSTL1 is subject to post-transcriptional regulation by tissue-specific miRNAs revealed it as a dynamically controlled gene rather than a constitutively expressed factor.\",\n      \"evidence\": \"miR-206 target site reporter assay and MyoD-driven fibroblast-to-muscle conversion showing miR-206 suppresses Fstl1 during skeletal muscle differentiation\",\n      \"pmids\": [\"17030984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether miR-206 regulation of FSTL1 operates in vivo during myogenesis was not tested\", \"Other miRNAs targeting FSTL1 were not surveyed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of DIP2A as a cell-surface receptor for FSTL1 established a direct signaling mechanism through which secreted FSTL1 activates Akt to promote endothelial survival and cardioprotection.\",\n      \"evidence\": \"Membrane fraction pull-down, reciprocal Co-IP, DIP2A siRNA ablation of FSTL1 binding and downstream Akt phosphorylation in endothelial cells and cardiomyocytes\",\n      \"pmids\": [\"20054002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FSTL1-DIP2A interaction unknown\", \"Whether DIP2A mediates all FSTL1 functions or only a subset was unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that FSTL1 directly binds BMP4 and functionally antagonizes BMP/Smad1/5/8 signaling in vivo resolved FSTL1's mechanism as a secreted BMP antagonist essential for lung morphogenesis.\",\n      \"evidence\": \"Fstl1 knockout mouse with pulmonary atelectasis, Co-IP of Fstl1 with BMP4, Noggin epistasis rescue restoring lung development\",\n      \"pmids\": [\"21482757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative affinities of FSTL1 for different BMP family ligands not determined\", \"Whether FSTL1 antagonism is stoichiometric or catalytic was unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that FSTL1 also directly binds the BMP type I receptor ALK6 expanded the antagonism mechanism beyond ligand sequestration to receptor-level inhibition.\",\n      \"evidence\": \"Direct binding assay of Fstl1 to ALK6, elevated pSmad1/5/8 in Fstl1-null ureters, Fstl1 knockout mouse ureter phenotype\",\n      \"pmids\": [\"22485132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FSTL1 blocks BMP-ALK6 association or alters receptor conformation was not distinguished\", \"Binding affinity not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of the TGF-β/KSRP-controlled molecular switch between miR-198 and FSTL1 protein from a shared transcript revealed an elegant post-transcriptional mechanism coupling wound healing signals to FSTL1 production.\",\n      \"evidence\": \"Human ex vivo skin organ culture, KSRP knockdown toggling miR-198/FSTL1 output, TGF-β pathway manipulation, migration assays\",\n      \"pmids\": [\"23395958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this switch operates in tissues beyond skin was not tested\", \"Quantitative kinetics of the switch in vivo unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A cluster of studies in 2017 expanded FSTL1's downstream signaling repertoire to include TLR4/NF-κB, autophagy/EMT, Smad3-c-Jun transcriptional regulation of Fstl1 itself, smooth muscle differentiation via myocardin/SRF, and competitive BMP4 sequestration from BMPR2 in glioma, revealing FSTL1 as a pleiotropic factor operating through multiple receptor-pathway axes in different tissues.\",\n      \"evidence\": \"Conditional Tie2-Cre KO (endocardium), OVA-challenged Fstl1 heterozygous mice (autophagy/EMT), Fstl1 promoter luciferase reporter (Smad3-c-Jun), BMP4-BMPR2 competition Co-IP (glioma), NF-κB/TLR4 inhibitor rescue (ESCC), myocardin/SRF loss in Fstl1 KO lungs\",\n      \"pmids\": [\"28705792\", \"28473327\", \"28495857\", \"29212066\", \"28883005\", \"28574994\", \"28827448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which receptor (DIP2A, TLR4, or others) mediates each tissue-specific effect not systematically resolved\", \"Relative contributions of BMP antagonism vs. TLR4 signaling in the same tissue not compared\", \"EGF-FSTL1-Wnt7a axis replicated only in HNSCC cells\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that FSTL1 sequesters DIP2A at the cell surface to prevent its nuclear HDAC2 complex formation revealed a non-canonical receptor-blocking mechanism linking FSTL1 to epigenetic regulation of chemoresistance.\",\n      \"evidence\": \"Co-IP of Fstl1 with DIP2A, subcellular fractionation, ChIP showing increased H3K9Ac at MGMT promoter upon FSTL1 exposure, DIP2A knockdown epistasis, glioblastoma xenograft\",\n      \"pmids\": [\"30542120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this DIP2A sequestration mechanism operates at other loci beyond MGMT not tested\", \"Structural basis of cytoplasmic DIP2A retention by FSTL1 undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The crystal structure of the FK domain revealed a stable dimer and established this domain as structurally and functionally indispensable for TGF-β signaling, providing the first structural framework for FSTL1 function.\",\n      \"evidence\": \"X-ray crystallography of murine Fstl1 FK domain, SEC-MALS confirming dimerization, FK domain deletion abolishing TGF-β signaling\",\n      \"pmids\": [\"31351024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length FSTL1 structure not solved\", \"Whether dimerization is required for receptor engagement unknown\", \"Structure of FSTL1 in complex with any binding partner not available\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two studies refined FSTL1's immunomodulatory and angiogenic roles: FSTL1 suppresses NF-κB via Nr4a1 in lung macrophages, and FSTL1 signals through DIP2A-Smad2/3 independently of TGFβR1 to drive cardiac angiogenesis.\",\n      \"evidence\": \"Recombinant FSTL1 macrophage treatment with Nr4a1-dependent NF-κB readout, FSTL1 hypomorphic mice with emphysema; AAV-FSTL1 in rat MI model with TGFβR1 inhibitor demonstrating DIP2A-Smad2/3 independence\",\n      \"pmids\": [\"31834999\", \"33246164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Nr4a1-FSTL1 binding not demonstrated\", \"Whether DIP2A-Smad2/3 and DIP2A-Akt are activated simultaneously or context-dependently not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Two discoveries in 2022 substantially expanded FSTL1's mechanism: its EC and VWC domains bridge Wnt ligands to Frizzled receptors to enhance Wnt/β-catenin signaling, and its FK domain binds intracellular PKM2 to reprogram macrophage glycolysis and drive M1 polarization, the latter representing the first intracellular signaling function of FSTL1.\",\n      \"evidence\": \"Domain deletion Co-IP mapping FSTL1-Wnt-FZD4 interactions, TOP/FOP reporter (kidney fibrosis model); myeloid-specific FSTL1 KO mice, FSTL1-PKM2 Co-IP, PKM2 phosphorylation/ubiquitination assays across three liver fibrosis models\",\n      \"pmids\": [\"35525270\", \"35140065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How secreted FSTL1 accesses intracellular PKM2 in macrophages not mechanistically explained\", \"Whether Wnt potentiation and BMP antagonism occur simultaneously in the same cell unclear\", \"Whether FSTL1-PKM2 interaction occurs in cell types beyond macrophages not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Recent work expanded FSTL1's transcriptional regulation (IRF4 in muscle), receptor usage (CD14 as an additional liver receptor), post-transcriptional stabilization (HuR), and downstream effectors (Src kinase for junction opening; SENP1 for deSUMOylation-dependent TGF-β amplification).\",\n      \"evidence\": \"Muscle-specific IRF4 KO with FSTL1 promoter luciferase and DIP2A/CD14 receptor assignment in liver cell types; HuR siRNA and Src inhibitor in HUVECs; SENP1 knockdown blocking FSTL1-induced senescence via Smad4/Ras deSUMOylation\",\n      \"pmids\": [\"37770480\", \"37694287\", \"37369969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CD14 as FSTL1 receptor demonstrated only in liver; generality unknown\", \"How FSTL1 upregulates SENP1 mechanistically not defined\", \"Whether H2S-HuR-FSTL1 axis operates outside endothelial cells not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Critical open questions include: the full-length FSTL1 structure and how domain architecture determines selective receptor engagement; how secreted FSTL1 accesses intracellular PKM2; the hierarchy among DIP2A, TLR4, CD14, and Frizzled as FSTL1 receptors in different tissues; and whether FSTL1 dimerization (via FK domain) is required for specific receptor interactions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length FSTL1 structure available\", \"Mechanism of FSTL1 intracellular access for PKM2 binding undefined\", \"Systematic receptor selectivity across tissues not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7, 10, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 3, 10, 11, 12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [1, 3, 7, 10, 12, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 7, 17, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 16, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 12, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BMP4\",\n      \"DIP2A\",\n      \"ALK6\",\n      \"PKM2\",\n      \"FZD4\",\n      \"TLR4\",\n      \"VIM\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}