{"gene":"INHBA","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2000,"finding":"Inhba encodes the βA subunit of activin A (homodimer) and activin AB (heterodimer with βB). Knock-in of Inhbb into the Inhba locus rescued craniofacial (whisker, palate, tooth) phenotypes of Inhba-null mice, demonstrating that spatial/temporal expression differences—not receptor specificity—underlie most Inhba-null phenotypes; novel somatic and gonadal phenotypes revealed additional activin A-specific functions.","method":"Gene knock-in (Inhbb coding region inserted into Inhba locus), genetic rescue experiment in mice, loss-of-function and dosage analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 — in vivo genetic reconstitution with multiple alleles and dosage series; 162 citations","pmids":["10932194"],"is_preprint":false},{"year":2015,"finding":"BDNF activates synaptic NMDA receptors, triggering nuclear-calcium signaling that transcriptionally upregulates Inhba (inhibin β-A). The resulting activin A reduces extrasynaptic NMDA-receptor-mediated calcium influx, protecting neurons from mitochondrial dysfunction and excitotoxicity. This nuclear-calcium–Inhba pathway confers neuroprotection against ischemic damage in a mouse stroke model.","method":"Nuclear calcium signaling blockade, siRNA knockdown of Inhba, recombinant activin A rescue, mouse stroke model (in vivo), calcium imaging","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (gene silencing, recombinant protein rescue, in vivo stroke model) in a single study; 75 citations","pmids":["26279570"],"is_preprint":false},{"year":2019,"finding":"INHBA silencing in gastric cancer cells inactivates the TGF-β signaling pathway, inhibiting cell migration, invasion, and proliferation, and reduces tumor xenograft growth in nude mice, placing INHBA upstream of TGF-β signaling in gastric cancer progression.","method":"shRNA-mediated INHBA knockdown, migration/invasion assays, tumor xenograft model in nude mice, pathway gene expression analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with in vitro and in vivo phenotypic readouts, but single lab","pmids":["30963572"],"is_preprint":false},{"year":2009,"finding":"Exogenous activin A (INHBA homodimer) promotes proliferation of esophageal adenocarcinoma cell lines, while follistatin (activin inhibitor) or INHBA-targeting siRNA reduces proliferation. INHBA expression in EAC cell lines is epigenetically regulated via promoter demethylation and histone acetylation (treatment with 5-AZA and trichostatin A upregulates INHBA mRNA and protein).","method":"Exogenous activin A treatment, follistatin inhibition, siRNA knockdown, 5-AZA/trichostatin A epigenetic treatment, RT-PCR, IHC","journal":"Journal of thoracic oncology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ligand addition, inhibitor, siRNA, epigenetic drugs) in single study","pmids":["19240652"],"is_preprint":false},{"year":2017,"finding":"Adrenergic signaling induces cancer cell production of INHBA (inhibin βA/activin A), which drives cancer-associated fibroblast (CAF) activation; ablating INHBA decreased the CAF phenotype both in vitro and in vivo in ovarian cancer models. This establishes INHBA as a mediator linking adrenergic stress signals to stromal remodeling.","method":"In vivo restraint-stress model, β-blocker pharmacological blockade, INHBA ablation (siRNA/shRNA), CAF activation assays in vitro and in vivo","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — systems approach with in vivo and in vitro validation, multiple cancer models, single lab","pmids":["28814667"],"is_preprint":false},{"year":2016,"finding":"miR-146a directly targets the 3′-UTR of INHBA to suppress its expression. INHBA overexpression rescued the miR-146a–induced reduction of M1 macrophage markers (IL-6, IL-12, TNF-α) and reversed the miR-146a–induced increase of M2 markers (Arg1, CCL17, CCL22), placing INHBA downstream of miR-146a as a regulator of macrophage polarization.","method":"3′-UTR luciferase reporter assay, miR-146a overexpression/knockdown, INHBA overexpression rescue experiments, macrophage polarization assays","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3′-UTR targeting confirmed with reporter assay plus rescue experiments; single lab","pmids":["27541693"],"is_preprint":false},{"year":2019,"finding":"INHBA knockdown in ovarian cancer cells impairs cancer xenograft growth by reducing stromal fibroblast activation in vivo. Mechanistically, Smad2 signaling is required for INHBA-induced fibroblast activation, and inhibiting this pathway reverses fibroblast activation.","method":"INHBA knockdown in cancer cells, xenograft model, fibroblast co-culture, Smad2 pathway inhibition","journal":"Disease markers","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo xenograft with defined pathway (Smad2) inhibition; single lab","pmids":["31827640"],"is_preprint":false},{"year":2022,"finding":"CircTHBS1 acts as a competing endogenous RNA (ceRNA) by sponging miR-204-5p, thereby de-repressing INHBA expression. Additionally, circTHBS1 enhances HuR-binding to INHBA mRNA, increasing its stability. Elevated INHBA subsequently activates the TGF-β pathway to promote gastric cancer malignancy.","method":"RNA pull-down, luciferase reporter assay, RNA immunoprecipitation (RIP), gain/loss-of-function assays, in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal RNA interaction methods (pull-down, RIP, luciferase) in single study","pmids":["35338119"],"is_preprint":false},{"year":2022,"finding":"Metformin specifically suppresses INHBA expression in colorectal cancer cells, blocking activation of TGF-β signaling, which downregulates PI3K/Akt activity and cyclin D1 levels, causing G1/S cell cycle arrest. INHBA knockdown phenocopies metformin's anti-proliferative effect; INHBA overexpression rescues proliferation.","method":"INHBA knockdown and overexpression in CRC cells, metformin treatment, cell cycle analysis, PI3K/Akt pathway readouts, Western blot","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function/loss-of-function with pathway readouts; single lab","pmids":["35236827"],"is_preprint":false},{"year":2023,"finding":"IGF2BP1 binds and stabilizes INHBA mRNA (m6A-dependent), increasing INHBA protein levels and activating Smad2/3 signaling to promote ESCC cell invasion and migration. G3BP1 interacts with IGF2BP1 to co-regulate this pathway. The small-molecule inhibitor BTYNB disrupts IGF2BP1–INHBA interaction and attenuates malignant phenotypes.","method":"RIP-seq, RNA pulldown, mass spectrometry, gene-specific m6A PCR, RNA stability assay, siRNA knockdown, immunofluorescence, in vivo metastasis assay","journal":"Experimental hematology & oncology","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal biochemical and functional methods (RIP-seq, pulldown, m6A, stability, in vivo) in single study","pmids":["37644505"],"is_preprint":false},{"year":2024,"finding":"INHBA/activin A in CAFs induces autocrine PD-L1 expression through SMAD2-dependent signaling. INHBA+ CAFs promote Treg differentiation through direct cell-to-cell contact. In ovarian cancer mouse models, neutralizing activin A antibody attenuated tumor progression and reduced pro-tumorigenic myofibroblast and macrophage infiltration.","method":"INHBA knockdown in human ovarian CAFs, T cell/CAF co-culture, activin A neutralizing antibody in vivo, SMAD2 signaling analysis, spatial transcriptomics of patient tumors","journal":"NPJ precision oncology","confidence":"High","confidence_rationale":"Tier 2 — multiple methods (KD, co-culture, in vivo antibody, patient spatial data) with mechanistic pathway (SMAD2→PD-L1) identified; single lab but strong","pmids":["38360876"],"is_preprint":false},{"year":2024,"finding":"Tumor-intrinsic INHBA/activin A suppresses the IFN-γ signaling pathway in the tumor microenvironment, leading to reduced IFN-γ-induced PD-L1 expression and decreased CXCL9/CXCL10 chemokine secretion, thereby impairing CD8+ T cell infiltration. INHBA overexpression abolishes anti-PD-L1 efficacy; INHBA deficiency enhances it. Garetosmab (activin A-specific antibody) combined with anti-PD-L1 shows superior anti-tumor effect.","method":"Gain/loss-of-function of Inhba in CT26, MC38, B16, 4T1 tumor models; IFN-γ signaling pathway analysis; anti-PD-L1 combination treatment in vivo; TIMER2.0 immune infiltration analysis","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vivo tumor models with defined IFN-γ pathway mechanism; single lab","pmids":["39223366"],"is_preprint":false},{"year":2020,"finding":"miR-211 directly targets INHBA (negatively regulating it), and overexpression of miR-211 or knockdown of INHBA reduces TGF-β pathway activation (TGF-β1, TGF-β2, Smad2, Smad3, phospho-Smad2/3) and decreases proliferation, invasion, colony-forming ability, sphere-forming, and stemness of prostate cancer stem cells in vitro and tumor growth in vivo.","method":"miR-211 overexpression/knockdown, INHBA siRNA knockdown, in vitro functional assays (proliferation, invasion, colony/sphere forming), in vivo tumor model","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined pathway (TGF-β/Smad) and in vivo validation; single lab","pmids":["33223523"],"is_preprint":false},{"year":2023,"finding":"miR-130b-3p directly targets and represses INHBA. miR-130b overexpression or siRNA-mediated knockdown of INHBA induces IL-8 expression (a potent angiogenic chemokine) and promotes revascularization in diabetic ischemic limb models in vivo, establishing a miR-130b/INHBA/IL-8 axis controlling angiogenesis.","method":"RNA-Seq, miRNA target prediction algorithms, siRNA knockdown of Inhba, miR-130b mimic delivery in vivo (db/db ischemic mice after FAL), angiogenesis assays, limb necrosis scoring","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo mechanistic validation (siRNA plus miRNA mimic), defined pathway; single lab","pmids":["37097749"],"is_preprint":false},{"year":2021,"finding":"INHBA induces EMT and accelerates breast cancer cell motility and invasion by activating TGF-β-regulated target genes. INHBA overexpression increases EMT marker expression (e.g., vimentin) and promotes migration; INHBA silencing reverses these effects.","method":"INHBA overexpression and siRNA silencing, wound-healing assay, transwell migration assay, EMT marker gene quantification (RT-qPCR, Western blot)","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 3 — gain/loss-of-function with phenotypic readouts but no in vivo validation; single lab","pmids":["34346300"],"is_preprint":false},{"year":2021,"finding":"INHBA knockdown in HER2+ basal breast cancer cells slows growth, increases lapatinib sensitivity, and shifts metabolism from glycolysis to oxidative phosphorylation, reducing tumor invasiveness. INHBA had no effect in luminal HER2+ cells, indicating subtype-specific function.","method":"siRNA knockdown screen, 2D and 3D cell culture, metabolic profiling, lapatinib sensitivity assay","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — phenotypic readout with metabolic mechanism defined, validated in multiple cell lines; single lab","pmids":["35248133"],"is_preprint":false},{"year":2021,"finding":"INHBA in cancer cells interacts with PEAK1-expressing mesenchymal stem cells/CAFs: INHBA/activin A is a necessary secreted factor in PEAK1+ MSC conditioned medium that promotes lapatinib resistance in HER2+ breast cancer, establishing a SNAI2–PEAK1–INHBA stromal axis.","method":"Conditioned medium experiments, PEAK1 knockdown, INHBA depletion, single-cell CycIF imaging, bioinformatic secretome analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — conditioned medium with target depletion identifies INHBA as necessary factor; single lab","pmids":["34239043"],"is_preprint":false},{"year":2024,"finding":"GLI1 transcriptionally upregulates INHBA, and elevated INHBA activates Smad signaling which in turn transcriptionally activates GLI1, forming a positive GLI1/INHBA feedback loop driving gastric cancer progression. Disrupting this interaction inhibits GC tumorigenesis in vivo.","method":"Transcriptional reporter assays, gain/loss-of-function, in vivo tumor model, Smad pathway analysis, H. pylori/FTO/YTHDF2/GLI1 m6A pathway analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional feedback loop established with in vivo validation; single lab","pmids":["38676428"],"is_preprint":false},{"year":2024,"finding":"FAP+ gastric cancer mesenchymal stromal cells secrete INHBA by paracrine signaling, activating SMAD2/3 pathway in gastric cancer cells to increase their proliferation and migration. Additionally, FAP+ GCMSCs induce collagen deposition in ECM, which activates Integrin β1 (ITGB1)→FAK→YAP signaling to promote invasion and stemness.","method":"ELISA, Western blot, conditioned medium experiments, flow cytometry-sorted FAP+ GCMSCs, transcriptomic sequencing, IHC, Masson staining","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — paracrine INHBA mechanism defined with SMAD2/3 readout and multiple methods; single lab","pmids":["39615112"],"is_preprint":false},{"year":2022,"finding":"miR-342-3p carried by BMSC-derived extracellular vesicles is transferred into breast cancer cells, downregulating INHBA expression. Reduced INHBA then represses IL13Rα2 expression. This INHBA/IL13Rα2 axis mediates BMSC-EV-induced suppression of breast cancer cell proliferation and metastasis in vitro and in vivo.","method":"Co-culture of EVs with MCF-7 cells, luciferase reporter assay, RNA pull-down, RIP assay, nude mouse tumorigenicity assay","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding confirmed by reporter/RIP/pulldown plus in vivo validation; single lab","pmids":["35093789"],"is_preprint":false},{"year":2024,"finding":"COL10A1 directly interacts with INHBA (by co-immunoprecipitation) in prostate cancer cells and facilitates PI3K and AKT phosphorylation. INHBA knockdown reverses the oncogenic effects (proliferation, migration, invasion) of COL10A1 overexpression, indicating INHBA is functionally downstream of COL10A1 in this signaling axis.","method":"Immunoprecipitation, Western blot for PI3K/AKT phosphorylation, CCK-8, colony formation, Transwell, flow cytometry, rescue experiment in cells and mouse models","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct physical interaction confirmed by Co-IP with functional rescue; single lab","pmids":["39656597"],"is_preprint":false},{"year":2025,"finding":"INHBA promotes gemcitabine resistance in pancreatic cancer by binding CTPS1 (cytidine triphosphate synthase 1) and competitively inhibiting SMURF1 (SMAD-specific E3 ubiquitin ligase)-mediated ubiquitination of CTPS1, thereby enhancing CTPS1 stability and promoting pyrimidine metabolism.","method":"Immunoprecipitation mass spectrometry, co-IP, ubiquitination assay, drug sensitivity analysis, colony formation, EdU, flow cytometry, xenograft model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 1/2 — biochemical interaction identified by IP-MS with ubiquitination mechanism validated; single lab","pmids":["41239468"],"is_preprint":false},{"year":2025,"finding":"KAT8 suppresses vascular senescence by regulating the INHBA/TGF-β/P15 signaling axis. KAT8 deficiency upregulates INHBA and exacerbates aging phenotypes; KAT8 overexpression attenuates vascular senescence. Multi-omics (miRNA-seq, ATAC-seq, RNA-seq) shows hsa-miR-339-3p drives age-related KAT8 downregulation.","method":"CRISPR-Cas9 loss/gain-of-function in endothelial cells and mice (C57BL/6J, ApoE-/-), multi-omics (miRNA-seq, ATAC-seq, RNA-seq), vascular senescence phenotyping","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics with in vivo CRISPR models, defined INHBA/TGF-β/P15 pathway; single lab","pmids":["41445196"],"is_preprint":false},{"year":2025,"finding":"INHBA confers 5-FU chemoresistance in colon cancer cells by facilitating cellular senescence through negative regulation (inactivation) of the Hippo signaling pathway. INHBA downregulation enhances 5-FU sensitivity, reduces senescent cell proportion and IL-6/IL-8 levels; the Hippo inhibitor verteporfin recapitulates INHBA's effects.","method":"INHBA knockdown, verteporfin (Hippo inhibitor) treatment, senescence assays (SA-β-gal), cell cycle analysis, xenograft model","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — pathway confirmed with specific inhibitor rescue experiment and in vivo model; single lab","pmids":["38588888"],"is_preprint":false},{"year":2025,"finding":"SPI1 transcription factor binds the INHBA promoter and transcriptionally activates INHBA expression in gastric cancer cells. INHBA then activates TGF-β signaling to upregulate CCL2, promoting macrophage recruitment and M2 polarization, which in turn facilitates GC cell proliferation, migration, and invasion.","method":"ChIP assay, dual-luciferase reporter, siRNA knockdown of INHBA and SPI1, ELISA for CCL2, macrophage polarization assays, in vivo xenograft","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional regulation confirmed by ChIP + reporter assay with functional downstream pathway; single lab","pmids":["40132395"],"is_preprint":false},{"year":2025,"finding":"C/EBPβ transcription factor upregulates INHBA expression in gastric cancer. INHBA promotes M2 macrophage polarization and activates the PI3K/AKT pathway, forming a PI3K/AKT/TGF-β positive feedback loop driving tumor progression and metastasis.","method":"ChIP, dual-luciferase reporter, CIBERSORT for immune infiltration, INHBA knockdown/overexpression, in vivo mouse model","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional regulation confirmed by ChIP/reporter with in vivo validation and positive feedback loop defined; single lab","pmids":["41540191"],"is_preprint":false},{"year":2025,"finding":"Extrasynaptic NMDA receptor (esNMDAR) activation extensively suppresses synaptic activity-regulated transcription including Inhba and Bdnf in hippocampal neurons. In a Huntington's disease mouse model, memantine or FP802 (targeting the NMDAR/TRPM4 complex) restored Inhba and Bdnf expression and attenuated the HD disease marker DARPP-32 loss, placing Inhba as a key neuroprotective gene regulated by the esNMDAR/CREB pathway.","method":"Primary hippocampal neuron cultures, pharmacological esNMDAR activation, memantine treatment, FP802 targeting NMDAR/TRPM4, HD mouse model, transcriptomic profiling","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — defined pathway with in vitro and in vivo disease models; single lab but orthogonal approaches","pmids":["41339520"],"is_preprint":false},{"year":2025,"finding":"INHBA promotes gastric cancer progression by targeting ITGA6 (Integrin α6) to activate the MAPK signaling pathway. INHBA and ITGA6 physical interaction was confirmed by Co-IP, and rescue experiments demonstrated that INHBA's pro-tumorigenic effects are mediated through ITGA6/MAPK.","method":"RNA-seq, Co-IP, co-immunofluorescence, Western blot, rescue assays, in vivo tumor model, RT-qPCR and IHC in clinical specimens","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 — physical interaction confirmed by Co-IP with pathway rescue experiments and in vivo validation; single lab","pmids":["41799510"],"is_preprint":false},{"year":2022,"finding":"Dysregulation of Inhba (elevated basal expression) and Npas4 (superinduction after learning) in DBA/2J mice is associated with altered excitation-inhibition balance in CA1 pyramidal neurons (fewer inhibitory, more excitatory miniature postsynaptic currents), linking Inhba expression levels to synaptic function and cognitive deficits.","method":"In vivo spatial object recognition task, IEG expression analysis, whole-cell patch-clamp electrophysiology, primary neuronal cultures","journal":"Learning & memory","confidence":"Low","confidence_rationale":"Tier 3 — correlative association between Inhba expression and electrophysiological phenotype; no direct manipulation of Inhba","pmids":["35042829"],"is_preprint":false},{"year":2025,"finding":"In a PCOS mouse model, Inhba is co-expressed with Smad2 and E2f4 in Lrp2-high thecal cells. siRNA-mediated knockdown of Inhba suppresses thecal cell proliferation in vitro (greatest effect among Inhba, Smad2, E2f4 knockdowns), indicating Inhba acts through Smad2 to drive E2f4-dependent cell cycle entry in thecal hyperplasia.","method":"Spatial transcriptomics, siRNA knockdown, EdU incorporation, flow cytometry (cell cycle), DHEA-induced PCOS mouse model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — spatial transcriptomics plus functional siRNA knockdown with defined axis (Inhba/Smad2/E2f4); single lab","pmids":["40831751"],"is_preprint":false},{"year":2025,"finding":"Mesenchyme-specific deletion of Gata2 reduces Inhba expression in the epididymal mesenchyme, leading to decreased epithelial proliferation and defective epididymal coiling. Dihydrotestosterone supplementation does not rescue the coiling defect, establishing that mesenchymal Gata2 promotes epididymal development through Inhba induction independently of androgen signaling.","method":"Conditional Gata2 knockout (mesenchyme-specific), DHT supplementation rescue experiment, epididymal morphometry, Inhba expression analysis","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with hormone rescue exclusion experiment in mouse; preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"In cochlear progenitor cells, TRIM71 represses Inhba and Tgfbr2 expression. Loss of TRIM71 leads to premature Inhba-mediated TGF-β signaling activation, causing early hair cell differentiation. InhbaTgfbr1 double-knockout mice indicate Inhba maintains hair cell progenitors in a proliferative, undifferentiated state by restricting TGF-β-type signaling.","method":"Conditional Trim71 KO in mice, Inhba/Tgfbr1 double-KO, transcriptomic profiling of cochlear progenitor cells, hair cell phenotyping, hearing tests","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis (double KO) with transcriptomic profiling defines Inhba as TRIM71 target regulating TGF-β pathway; preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Integrin α2 (Itgα2) links collagen I engagement to INHBA expression induction in basal-like cancer cells, activating TGF-β signaling which upregulates vimentin while preserving epithelial junction gene expression (partial EMT). Itgα2 also promotes ECM degradation through a TGF-β-independent mechanism, identifying an Itgα2→INHBA→TGFβ axis as a regulator of leader cell function in collective invasion.","method":"Collagen I-responsive cell subset identification, Itgα2 manipulation, INHBA expression measurement, TGFβ pathway inhibition, vimentin/junction gene expression analysis","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 — pathway induction described but mechanistic details of Itgα2→INHBA link not fully biochemically established; preprint, single lab","pmids":[],"is_preprint":true}],"current_model":"INHBA encodes the inhibin βA subunit that homodimerizes to form activin A (or heterodimerizes to form activin AB or inhibin A), and functions primarily as a TGF-β superfamily ligand that signals through SMAD2/3 to regulate cell proliferation, EMT, invasion, fibroblast activation, macrophage polarization, immune suppression (via PD-L1 and IFN-γ pathway suppression), and neuroprotection (via nuclear calcium-driven transcription downstream of synaptic NMDA receptors); its mRNA stability is post-transcriptionally regulated by RNA-binding proteins (IGF2BP1, HuR) and miRNAs, while its transcription is regulated by factors including SPI1, C/EBPβ, BHLHE40, and GLI1."},"narrative":{"teleology":[{"year":2000,"claim":"Knock-in of Inhbb into the Inhba locus demonstrated that most Inhba-null phenotypes (craniofacial defects) arise from spatial/temporal expression differences rather than ligand-receptor specificity, while also revealing activin A-specific roles in somatic and gonadal tissues that Inhbb cannot substitute.","evidence":"Gene knock-in rescue in mice with dosage analysis","pmids":["10932194"],"confidence":"High","gaps":["Molecular basis of activin A-specific (non-rescuable) functions undefined","Receptor-level selectivity versus co-receptor usage not resolved"]},{"year":2009,"claim":"Activin A was established as a proliferative signal in epithelial cancer cells, with INHBA expression shown to be epigenetically regulated through promoter methylation and histone acetylation, providing the first mechanistic link between epigenetic derepression and activin-driven tumor growth.","evidence":"Exogenous activin A, follistatin inhibition, INHBA siRNA, and 5-AZA/TSA treatment in esophageal adenocarcinoma cells","pmids":["19240652"],"confidence":"Medium","gaps":["Specific histone marks and demethylases at INHBA promoter not identified","In vivo validation of epigenetic regulation lacking"]},{"year":2015,"claim":"A neuroprotective circuit was delineated in which BDNF-activated synaptic NMDA receptors trigger nuclear calcium signaling to induce INHBA transcription, and the resulting activin A attenuates extrasynaptic NMDA receptor calcium influx, protecting neurons from excitotoxicity and ischemic injury.","evidence":"Nuclear calcium blockade, Inhba siRNA, recombinant activin A rescue, calcium imaging, mouse stroke model","pmids":["26279570"],"confidence":"High","gaps":["Mechanism by which activin A reduces extrasynaptic NMDA receptor activity not defined at the molecular level","Downstream transcriptional targets in neurons not identified"]},{"year":2016,"claim":"INHBA was placed as a downstream effector of miR-146a in macrophage polarization, showing that activin A promotes M1 and suppresses M2 macrophage markers — the first direct evidence for INHBA controlling innate immune cell phenotype via a specific miRNA regulatory input.","evidence":"3′-UTR luciferase reporter, miR-146a overexpression/knockdown, INHBA rescue in macrophages","pmids":["27541693"],"confidence":"Medium","gaps":["Signaling pathway downstream of INHBA in macrophage polarization not specified","In vivo relevance not tested"]},{"year":2017,"claim":"INHBA was identified as a key paracrine mediator linking adrenergic stress to cancer-associated fibroblast activation, establishing the concept that tumor cell-derived activin A remodels the stroma.","evidence":"Restraint-stress model, β-blocker treatment, INHBA ablation in ovarian cancer in vitro and in vivo","pmids":["28814667"],"confidence":"Medium","gaps":["Adrenergic receptor subtype and transcriptional pathway leading to INHBA induction not defined","Whether fibroblast activation is SMAD-dependent not tested in this study"]},{"year":2019,"claim":"SMAD2 was identified as the required downstream effector of INHBA-mediated fibroblast activation in ovarian cancer, and INHBA knockdown in gastric cancer confirmed TGF-β pathway dependence for proliferation, migration, and invasion, solidifying SMAD2/3 as the canonical intracellular pathway for activin A's pro-tumorigenic effects.","evidence":"INHBA knockdown, Smad2 pathway inhibition, tumor xenografts in gastric and ovarian cancer","pmids":["31827640","30963572"],"confidence":"Medium","gaps":["Non-SMAD signaling contributions (e.g., MAPK, PI3K) not excluded","Identity of activin receptor complexes on fibroblasts not characterized"]},{"year":2020,"claim":"miR-211 was shown to directly repress INHBA, and its loss led to enhanced TGF-β/Smad2/3 activation and cancer stemness in prostate cancer, adding a second miRNA regulatory axis and linking INHBA to stem cell properties.","evidence":"miR-211 overexpression/knockdown, INHBA siRNA, sphere-forming assay, in vivo tumor model","pmids":["33223523"],"confidence":"Medium","gaps":["Mechanism by which INHBA/activin A promotes stemness transcription factors unknown","Interaction with androgen receptor signaling not tested"]},{"year":2021,"claim":"INHBA was demonstrated to induce EMT in breast cancer and to be a necessary factor in PEAK1+ mesenchymal stromal cell conditioned medium conferring lapatinib resistance, establishing activin A as a mediator of both intrinsic motility programs and therapy resistance through stromal interactions.","evidence":"INHBA overexpression/silencing for EMT markers; conditioned medium depletion identifying INHBA as required for PEAK1-mediated lapatinib resistance; metabolic profiling showing glycolysis dependence","pmids":["34346300","34239043","35248133"],"confidence":"Medium","gaps":["Direct receptor engagement on cancer cells not shown","Whether EMT and drug resistance share the same SMAD pathway branch unclear"]},{"year":2022,"claim":"Post-transcriptional regulation of INHBA mRNA was mechanistically defined: circTHBS1 sponges miR-204-5p to de-repress INHBA, and additionally recruits HuR to stabilize INHBA mRNA, connecting non-coding RNA networks to INHBA-driven TGF-β activation in gastric cancer. Separately, metformin was shown to suppress INHBA to block PI3K/Akt/cyclin D1 and induce G1/S arrest in colorectal cancer.","evidence":"RNA pull-down, RIP, luciferase reporter for circTHBS1/miR-204-5p/HuR axis; INHBA knockdown/overexpression with metformin and cell cycle analysis","pmids":["35338119","35236827"],"confidence":"Medium","gaps":["Whether HuR binding is m6A-dependent or independent not resolved","Metformin's direct target leading to INHBA suppression not identified"]},{"year":2023,"claim":"IGF2BP1 was identified as an m6A-dependent stabilizer of INHBA mRNA that cooperates with G3BP1, directly linking epitranscriptomic regulation to INHBA protein output and Smad2/3-driven invasion in esophageal squamous cell carcinoma. Separately, a miR-130b-3p/INHBA/IL-8 axis was shown to control angiogenesis in diabetic ischemia.","evidence":"RIP-seq, RNA pulldown, m6A-specific PCR, BTYNB inhibitor for IGF2BP1; miR-130b mimic in vivo in ischemic limb model","pmids":["37644505","37097749"],"confidence":"High","gaps":["Specific m6A writer depositing marks on INHBA mRNA not identified","Whether IGF2BP1 and HuR compete or cooperate on INHBA mRNA unclear"]},{"year":2024,"claim":"INHBA's immunoregulatory functions were resolved at two levels: in cancer-associated fibroblasts, activin A induces autocrine PD-L1 via SMAD2 and promotes Treg differentiation through cell contact; in tumor cells, INHBA suppresses IFN-γ signaling to reduce CXCL9/CXCL10 and impair CD8+ T cell infiltration, explaining resistance to anti-PD-L1 therapy that is reversible by activin A neutralization.","evidence":"INHBA knockdown in CAFs, T cell co-culture, anti-activin A antibody in vivo, spatial transcriptomics; Inhba gain/loss-of-function across four syngeneic tumor models with IFN-γ pathway analysis","pmids":["38360876","39223366"],"confidence":"High","gaps":["Whether SMAD2-dependent PD-L1 induction and IFN-γ suppression are the same or distinct mechanisms is unresolved","Activin receptor expression pattern across immune cell subsets not characterized"]},{"year":2024,"claim":"Transcriptional regulation of INHBA was mapped: GLI1 directly activates INHBA transcription, and Smad-mediated feedback transcriptionally reactivates GLI1, creating a positive feedback loop in gastric cancer; FAP+ mesenchymal stromal cells secrete INHBA to activate SMAD2/3 in neighboring cancer cells.","evidence":"ChIP and reporter assays for GLI1; ELISA and conditioned medium with FAP+ sorted stromal cells; in vivo gastric cancer models","pmids":["38676428","39615112"],"confidence":"Medium","gaps":["How the GLI1/INHBA feedback loop is initiated and terminated not defined","Relative contribution of stromal vs. tumor-intrinsic INHBA unclear"]},{"year":2025,"claim":"Multiple transcriptional inputs to INHBA were confirmed: SPI1 binds the INHBA promoter to drive CCL2-mediated macrophage recruitment, and C/EBPβ activates INHBA to establish a PI3K/AKT/TGF-β positive feedback loop, while KAT8 deficiency de-represses INHBA contributing to vascular senescence through TGF-β/P15 signaling.","evidence":"ChIP and dual-luciferase reporters for SPI1 and C/EBPβ; CRISPR KAT8 KO with multi-omics in endothelial cells and mice","pmids":["40132395","41540191","41445196"],"confidence":"Medium","gaps":["How multiple transcription factors (SPI1, C/EBPβ, GLI1, KAT8) are hierarchically organized at the INHBA promoter is unknown","Chromatin state and enhancer architecture at the INHBA locus not mapped"]},{"year":2025,"claim":"A non-canonical intracellular function for INHBA protein was uncovered: INHBA binds CTPS1 and competitively inhibits SMURF1-mediated ubiquitination of CTPS1, stabilizing it to enhance pyrimidine metabolism and gemcitabine resistance in pancreatic cancer. Additionally, INHBA binds ITGA6 to activate MAPK signaling in gastric cancer, and interacts with COL10A1 to activate PI3K/AKT in prostate cancer.","evidence":"IP-mass spectrometry, co-IP, ubiquitination assay, BTYNB for CTPS1 axis; co-IP and rescue for ITGA6/MAPK and COL10A1/PI3K/AKT","pmids":["41239468","41799510","39656597"],"confidence":"Medium","gaps":["Whether INHBA–CTPS1 interaction occurs intracellularly or extracellularly is unclear","INHBA interaction with ITGA6 and COL10A1 each shown by single-lab co-IP without reciprocal or structural validation","Relationship between these non-canonical interactions and classical activin receptor signaling not clarified"]},{"year":2025,"claim":"Extrasynaptic NMDA receptor activation suppresses Inhba transcription in hippocampal neurons, and pharmacological restoration (memantine, FP802) of Inhba expression attenuated neurodegeneration in a Huntington's disease mouse model, extending the neuroprotective role of INHBA beyond ischemia to chronic neurodegeneration.","evidence":"Pharmacological esNMDAR activation, memantine and FP802 treatment, HD mouse model, transcriptomic profiling","pmids":["41339520"],"confidence":"Medium","gaps":["Whether activin A protein levels and secretion are restored in vivo not measured","Downstream neuroprotective effectors of activin A in HD context not identified"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of activin A interactions with non-canonical partners (CTPS1, ITGA6, COL10A1); how multiple transcription factors and post-transcriptional regulators are integrated at the INHBA locus in different cell types; the relative contributions of autocrine versus paracrine activin A signaling in the tumor microenvironment; and whether the intracellular/non-canonical functions of INHBA protein are independent of its secreted ligand role.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data for INHBA interactions with CTPS1, ITGA6, or COL10A1","Relative autocrine vs. paracrine contribution of INHBA in tumors not quantified","Whether intracellular INHBA functions require dimerization is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,3,4,6,10,11,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[21,23]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,8,14,17]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,4,10,11,18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6,8,9,10,11,12,17,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,10,11,24,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,8,14,21,23]}],"complexes":["Activin A (βA homodimer)","Activin AB (βA/βB heterodimer)","Inhibin A (α/βA heterodimer)"],"partners":["SMAD2","SMAD3","IGF2BP1","G3BP1","CTPS1","COL10A1","ITGA6","ELAVL1"],"other_free_text":[]},"mechanistic_narrative":"INHBA encodes the inhibin βA subunit, which homodimerizes to form activin A, a secreted TGF-β superfamily ligand that signals through SMAD2/3 to regulate cell proliferation, epithelial-mesenchymal transition, fibroblast activation, macrophage polarization, and immune evasion across diverse tissue contexts [PMID:10932194, PMID:30963572, PMID:31827640, PMID:38360876]. Activin A drives cancer-associated fibroblast activation via paracrine SMAD2 signaling, induces PD-L1 expression on fibroblasts, promotes Treg differentiation, and suppresses IFN-γ-dependent CD8+ T cell recruitment through downregulation of CXCL9/CXCL10, thereby shaping an immunosuppressive tumor microenvironment [PMID:28814667, PMID:38360876, PMID:39223366]. In neurons, nuclear calcium signaling downstream of synaptic NMDA receptors transcriptionally induces INHBA, and the resulting activin A reduces extrasynaptic NMDA receptor-mediated calcium influx to confer neuroprotection against excitotoxicity and ischemic injury [PMID:26279570, PMID:41339520]. INHBA mRNA stability is post-transcriptionally regulated by IGF2BP1 in an m6A-dependent manner and by HuR, while its transcription is controlled by SPI1, C/EBPβ, GLI1, and KAT8, and it is repressed by multiple miRNAs including miR-146a, miR-211, miR-130b-3p, and miR-342-3p [PMID:37644505, PMID:35338119, PMID:27541693, PMID:40132395, PMID:41540191]."},"prefetch_data":{"uniprot":{"accession":"P08476","full_name":"Inhibin beta A chain","aliases":["Activin beta-A chain","Erythroid differentiation protein","EDF"],"length_aa":426,"mass_kda":47.4,"function":"Inhibins/activins are involved in regulating a number of diverse functions such as hypothalamic and pituitary hormone secretion, gonadal hormone secretion, germ cell development and maturation, erythroid differentiation, insulin secretion, nerve cell survival, embryonic axial development or bone growth, depending on their subunit composition Activin A is a homodimer of INHBA that plays a role in several essential biological processes including embryonic development, stem cell maintenance and differentiation, haematopoiesis, cell proliferation and tissue fibrosis (PubMed:3194407, PubMed:16440334). Signals through type I (such as ACVR1B or ACVR1C) and type II receptors (such as ACVR2A, ACVR2B or BMPR2) which, upon ligand binding, phosphorylate SMAD2 and SMAD3 intracellular signaling mediators that form a complex with SMAD4, translocate to the nucleus and modulate gene expression (PubMed:10652306, PubMed:24018044). Can also activate alternative non-canonical intracellular signaling pathways including the p38 MAPK, extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal kinases (JNKs) to modulate cell migration and differentiation (PubMed:16440334). Alternatively, promotes osteoblastic differentiation via ACVRL1-SMAD1/5/9 pathway (PubMed:34948289). In addition, can engage the type I receptor ACVR1 to form an ACVR1-activin A-type II receptor non-signaling complex (NSC) that renders receptors unavailable for engagement with BMPs, hence resulting in an apparent inhibition of ACVR1-mediated BMP signaling (PubMed:26333933) Inhibin A is a dimer of alpha/INHA and beta-A/INHBA that functions as a feedback regulator in the hypothalamic-pituitary-gonadal (HPG) axis. Inhibits the secretion of FSH from the anterior pituitary gland by acting on pituitary gonadotrope cells. Antagonizes activin A by binding to the proteoglycan, betaglycan, and forming a stable complex with and, thereby, sequestering type II activin receptors while excluding type I receptor","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P08476/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INHBA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/INHBA","total_profiled":1310},"omim":[{"mim_id":"612883","title":"MENARCHE, AGE AT, QUANTITATIVE TRAIT LOCUS 3; MENAQ3","url":"https://www.omim.org/entry/612883"},{"mim_id":"612882","title":"MENARCHE, AGE AT, QUANTITATIVE TRAIT LOCUS 2; MENAQ2","url":"https://www.omim.org/entry/612882"},{"mim_id":"612031","title":"INHIBIN, BETA E; INHBE","url":"https://www.omim.org/entry/612031"},{"mim_id":"610655","title":"TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 4; HHT4","url":"https://www.omim.org/entry/610655"},{"mim_id":"300137","title":"IMMUNOGLOBULIN SUPERFAMILY, MEMBER 1; IGSF1","url":"https://www.omim.org/entry/300137"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":18.6},{"tissue":"gallbladder","ntpm":20.2}],"url":"https://www.proteinatlas.org/search/INHBA"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P08476","domains":[{"cath_id":"2.10.90.10","chopping":"50-114_309-354_390-424","consensus_level":"high","plddt":88.7034,"start":50,"end":424},{"cath_id":"2.60.120","chopping":"128-180_201-258_286-290","consensus_level":"high","plddt":89.2078,"start":128,"end":290}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08476","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08476-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08476-F1-predicted_aligned_error_v6.png","plddt_mean":76.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INHBA","jax_strain_url":"https://www.jax.org/strain/search?query=INHBA"},"sequence":{"accession":"P08476","fasta_url":"https://rest.uniprot.org/uniprotkb/P08476.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08476/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08476"}},"corpus_meta":[{"pmid":"10932194","id":"PMC_10932194","title":"Insertion 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of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19240652","citation_count":56,"is_preprint":false},{"pmid":"33429081","id":"PMC_33429081","title":"TGFB1/INHBA Homodimer/Nodal-SMAD2/3 Signaling Network: A Pivotal Molecular Target in PDAC Treatment.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33429081","citation_count":50,"is_preprint":false},{"pmid":"34346300","id":"PMC_34346300","title":"Inhibin β-A (INHBA) induces epithelial-mesenchymal transition and accelerates the motility of breast cancer cells by activating the TGF-β signaling pathway.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34346300","citation_count":45,"is_preprint":false},{"pmid":"28814667","id":"PMC_28814667","title":"Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens.","date":"2017","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/28814667","citation_count":40,"is_preprint":false},{"pmid":"33230466","id":"PMC_33230466","title":"Preeclampsia-Associated lncRNA INHBA-AS1 Regulates the Proliferation, Invasion, and Migration of Placental Trophoblast Cells.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/33230466","citation_count":34,"is_preprint":false},{"pmid":"38360876","id":"PMC_38360876","title":"INHBA(+) cancer-associated fibroblasts generate an immunosuppressive tumor microenvironment in ovarian cancer.","date":"2024","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38360876","citation_count":33,"is_preprint":false},{"pmid":"34130530","id":"PMC_34130530","title":"INHBA promotes the proliferation, migration and invasion of colon cancer cells through the upregulation of VCAN.","date":"2021","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/34130530","citation_count":29,"is_preprint":false},{"pmid":"34537472","id":"PMC_34537472","title":"INHBA transfection regulates proliferation, apoptosis and hormone synthesis in sheep granulosa cells.","date":"2021","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/34537472","citation_count":28,"is_preprint":false},{"pmid":"37644505","id":"PMC_37644505","title":"Elevated expression of the RNA-binding protein IGF2BP1 enhances the mRNA stability of INHBA to promote the invasion and migration of esophageal squamous cancer cells.","date":"2023","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37644505","citation_count":27,"is_preprint":false},{"pmid":"31827640","id":"PMC_31827640","title":"Targeting INHBA in Ovarian Cancer Cells Suppresses Cancer Xenograft Growth by Attenuating Stromal Fibroblast Activation.","date":"2019","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/31827640","citation_count":27,"is_preprint":false},{"pmid":"34239043","id":"PMC_34239043","title":"A SNAI2-PEAK1-INHBA stromal axis drives progression and lapatinib resistance in HER2-positive breast cancer by supporting subpopulations of tumor cells positive for antiapoptotic and stress signaling markers.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34239043","citation_count":25,"is_preprint":false},{"pmid":"34476008","id":"PMC_34476008","title":"INHBA is a novel mediator regulating cellular senescence and immune evasion in colorectal cancer.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34476008","citation_count":21,"is_preprint":false},{"pmid":"38735606","id":"PMC_38735606","title":"Discovery of PELATON links to the INHBA gene in the TGF-β pathway in colorectal cancer using a combination of bioinformatics and experimental investigations.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38735606","citation_count":19,"is_preprint":false},{"pmid":"19144026","id":"PMC_19144026","title":"INHBA-associated markers as candidates for stallion fertility.","date":"2009","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/19144026","citation_count":19,"is_preprint":false},{"pmid":"39223366","id":"PMC_39223366","title":"INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling.","date":"2024","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/39223366","citation_count":16,"is_preprint":false},{"pmid":"35689549","id":"PMC_35689549","title":"Upregulation of INHBA mediated by the transcription factor BHLHE40 promotes colon cancer cell proliferation and migration.","date":"2022","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/35689549","citation_count":16,"is_preprint":false},{"pmid":"31586103","id":"PMC_31586103","title":"Expression and gene regulation network of INHBA in Head and neck squamous cell carcinoma based on data mining.","date":"2019","source":"Scientific 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pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32509056","citation_count":14,"is_preprint":false},{"pmid":"35248133","id":"PMC_35248133","title":"INHBA is a mediator of aggressive tumor behavior in HER2+ basal breast cancer.","date":"2022","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/35248133","citation_count":14,"is_preprint":false},{"pmid":"35521936","id":"PMC_35521936","title":"Comprehensive analysis of INHBA: A biomarker for anti-TGFβ treatment in head and neck cancer.","date":"2022","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/35521936","citation_count":13,"is_preprint":false},{"pmid":"33223523","id":"PMC_33223523","title":"microRNA-211-mediated targeting of the INHBA-TGF-β axis suppresses prostate tumor formation and growth.","date":"2020","source":"Cancer gene 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Knock-in of Inhbb into the Inhba locus rescued craniofacial (whisker, palate, tooth) phenotypes of Inhba-null mice, demonstrating that spatial/temporal expression differences—not receptor specificity—underlie most Inhba-null phenotypes; novel somatic and gonadal phenotypes revealed additional activin A-specific functions.\",\n      \"method\": \"Gene knock-in (Inhbb coding region inserted into Inhba locus), genetic rescue experiment in mice, loss-of-function and dosage analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo genetic reconstitution with multiple alleles and dosage series; 162 citations\",\n      \"pmids\": [\"10932194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BDNF activates synaptic NMDA receptors, triggering nuclear-calcium signaling that transcriptionally upregulates Inhba (inhibin β-A). The resulting activin A reduces extrasynaptic NMDA-receptor-mediated calcium influx, protecting neurons from mitochondrial dysfunction and excitotoxicity. This nuclear-calcium–Inhba pathway confers neuroprotection against ischemic damage in a mouse stroke model.\",\n      \"method\": \"Nuclear calcium signaling blockade, siRNA knockdown of Inhba, recombinant activin A rescue, mouse stroke model (in vivo), calcium imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (gene silencing, recombinant protein rescue, in vivo stroke model) in a single study; 75 citations\",\n      \"pmids\": [\"26279570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"INHBA silencing in gastric cancer cells inactivates the TGF-β signaling pathway, inhibiting cell migration, invasion, and proliferation, and reduces tumor xenograft growth in nude mice, placing INHBA upstream of TGF-β signaling in gastric cancer progression.\",\n      \"method\": \"shRNA-mediated INHBA knockdown, migration/invasion assays, tumor xenograft model in nude mice, pathway gene expression analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with in vitro and in vivo phenotypic readouts, but single lab\",\n      \"pmids\": [\"30963572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Exogenous activin A (INHBA homodimer) promotes proliferation of esophageal adenocarcinoma cell lines, while follistatin (activin inhibitor) or INHBA-targeting siRNA reduces proliferation. INHBA expression in EAC cell lines is epigenetically regulated via promoter demethylation and histone acetylation (treatment with 5-AZA and trichostatin A upregulates INHBA mRNA and protein).\",\n      \"method\": \"Exogenous activin A treatment, follistatin inhibition, siRNA knockdown, 5-AZA/trichostatin A epigenetic treatment, RT-PCR, IHC\",\n      \"journal\": \"Journal of thoracic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ligand addition, inhibitor, siRNA, epigenetic drugs) in single study\",\n      \"pmids\": [\"19240652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adrenergic signaling induces cancer cell production of INHBA (inhibin βA/activin A), which drives cancer-associated fibroblast (CAF) activation; ablating INHBA decreased the CAF phenotype both in vitro and in vivo in ovarian cancer models. This establishes INHBA as a mediator linking adrenergic stress signals to stromal remodeling.\",\n      \"method\": \"In vivo restraint-stress model, β-blocker pharmacological blockade, INHBA ablation (siRNA/shRNA), CAF activation assays in vitro and in vivo\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systems approach with in vivo and in vitro validation, multiple cancer models, single lab\",\n      \"pmids\": [\"28814667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-146a directly targets the 3′-UTR of INHBA to suppress its expression. INHBA overexpression rescued the miR-146a–induced reduction of M1 macrophage markers (IL-6, IL-12, TNF-α) and reversed the miR-146a–induced increase of M2 markers (Arg1, CCL17, CCL22), placing INHBA downstream of miR-146a as a regulator of macrophage polarization.\",\n      \"method\": \"3′-UTR luciferase reporter assay, miR-146a overexpression/knockdown, INHBA overexpression rescue experiments, macrophage polarization assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3′-UTR targeting confirmed with reporter assay plus rescue experiments; single lab\",\n      \"pmids\": [\"27541693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"INHBA knockdown in ovarian cancer cells impairs cancer xenograft growth by reducing stromal fibroblast activation in vivo. Mechanistically, Smad2 signaling is required for INHBA-induced fibroblast activation, and inhibiting this pathway reverses fibroblast activation.\",\n      \"method\": \"INHBA knockdown in cancer cells, xenograft model, fibroblast co-culture, Smad2 pathway inhibition\",\n      \"journal\": \"Disease markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo xenograft with defined pathway (Smad2) inhibition; single lab\",\n      \"pmids\": [\"31827640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircTHBS1 acts as a competing endogenous RNA (ceRNA) by sponging miR-204-5p, thereby de-repressing INHBA expression. Additionally, circTHBS1 enhances HuR-binding to INHBA mRNA, increasing its stability. Elevated INHBA subsequently activates the TGF-β pathway to promote gastric cancer malignancy.\",\n      \"method\": \"RNA pull-down, luciferase reporter assay, RNA immunoprecipitation (RIP), gain/loss-of-function assays, in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal RNA interaction methods (pull-down, RIP, luciferase) in single study\",\n      \"pmids\": [\"35338119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Metformin specifically suppresses INHBA expression in colorectal cancer cells, blocking activation of TGF-β signaling, which downregulates PI3K/Akt activity and cyclin D1 levels, causing G1/S cell cycle arrest. INHBA knockdown phenocopies metformin's anti-proliferative effect; INHBA overexpression rescues proliferation.\",\n      \"method\": \"INHBA knockdown and overexpression in CRC cells, metformin treatment, cell cycle analysis, PI3K/Akt pathway readouts, Western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function/loss-of-function with pathway readouts; single lab\",\n      \"pmids\": [\"35236827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP1 binds and stabilizes INHBA mRNA (m6A-dependent), increasing INHBA protein levels and activating Smad2/3 signaling to promote ESCC cell invasion and migration. G3BP1 interacts with IGF2BP1 to co-regulate this pathway. The small-molecule inhibitor BTYNB disrupts IGF2BP1–INHBA interaction and attenuates malignant phenotypes.\",\n      \"method\": \"RIP-seq, RNA pulldown, mass spectrometry, gene-specific m6A PCR, RNA stability assay, siRNA knockdown, immunofluorescence, in vivo metastasis assay\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal biochemical and functional methods (RIP-seq, pulldown, m6A, stability, in vivo) in single study\",\n      \"pmids\": [\"37644505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"INHBA/activin A in CAFs induces autocrine PD-L1 expression through SMAD2-dependent signaling. INHBA+ CAFs promote Treg differentiation through direct cell-to-cell contact. In ovarian cancer mouse models, neutralizing activin A antibody attenuated tumor progression and reduced pro-tumorigenic myofibroblast and macrophage infiltration.\",\n      \"method\": \"INHBA knockdown in human ovarian CAFs, T cell/CAF co-culture, activin A neutralizing antibody in vivo, SMAD2 signaling analysis, spatial transcriptomics of patient tumors\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (KD, co-culture, in vivo antibody, patient spatial data) with mechanistic pathway (SMAD2→PD-L1) identified; single lab but strong\",\n      \"pmids\": [\"38360876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tumor-intrinsic INHBA/activin A suppresses the IFN-γ signaling pathway in the tumor microenvironment, leading to reduced IFN-γ-induced PD-L1 expression and decreased CXCL9/CXCL10 chemokine secretion, thereby impairing CD8+ T cell infiltration. INHBA overexpression abolishes anti-PD-L1 efficacy; INHBA deficiency enhances it. Garetosmab (activin A-specific antibody) combined with anti-PD-L1 shows superior anti-tumor effect.\",\n      \"method\": \"Gain/loss-of-function of Inhba in CT26, MC38, B16, 4T1 tumor models; IFN-γ signaling pathway analysis; anti-PD-L1 combination treatment in vivo; TIMER2.0 immune infiltration analysis\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo tumor models with defined IFN-γ pathway mechanism; single lab\",\n      \"pmids\": [\"39223366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-211 directly targets INHBA (negatively regulating it), and overexpression of miR-211 or knockdown of INHBA reduces TGF-β pathway activation (TGF-β1, TGF-β2, Smad2, Smad3, phospho-Smad2/3) and decreases proliferation, invasion, colony-forming ability, sphere-forming, and stemness of prostate cancer stem cells in vitro and tumor growth in vivo.\",\n      \"method\": \"miR-211 overexpression/knockdown, INHBA siRNA knockdown, in vitro functional assays (proliferation, invasion, colony/sphere forming), in vivo tumor model\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined pathway (TGF-β/Smad) and in vivo validation; single lab\",\n      \"pmids\": [\"33223523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-130b-3p directly targets and represses INHBA. miR-130b overexpression or siRNA-mediated knockdown of INHBA induces IL-8 expression (a potent angiogenic chemokine) and promotes revascularization in diabetic ischemic limb models in vivo, establishing a miR-130b/INHBA/IL-8 axis controlling angiogenesis.\",\n      \"method\": \"RNA-Seq, miRNA target prediction algorithms, siRNA knockdown of Inhba, miR-130b mimic delivery in vivo (db/db ischemic mice after FAL), angiogenesis assays, limb necrosis scoring\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo mechanistic validation (siRNA plus miRNA mimic), defined pathway; single lab\",\n      \"pmids\": [\"37097749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INHBA induces EMT and accelerates breast cancer cell motility and invasion by activating TGF-β-regulated target genes. INHBA overexpression increases EMT marker expression (e.g., vimentin) and promotes migration; INHBA silencing reverses these effects.\",\n      \"method\": \"INHBA overexpression and siRNA silencing, wound-healing assay, transwell migration assay, EMT marker gene quantification (RT-qPCR, Western blot)\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — gain/loss-of-function with phenotypic readouts but no in vivo validation; single lab\",\n      \"pmids\": [\"34346300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INHBA knockdown in HER2+ basal breast cancer cells slows growth, increases lapatinib sensitivity, and shifts metabolism from glycolysis to oxidative phosphorylation, reducing tumor invasiveness. INHBA had no effect in luminal HER2+ cells, indicating subtype-specific function.\",\n      \"method\": \"siRNA knockdown screen, 2D and 3D cell culture, metabolic profiling, lapatinib sensitivity assay\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phenotypic readout with metabolic mechanism defined, validated in multiple cell lines; single lab\",\n      \"pmids\": [\"35248133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INHBA in cancer cells interacts with PEAK1-expressing mesenchymal stem cells/CAFs: INHBA/activin A is a necessary secreted factor in PEAK1+ MSC conditioned medium that promotes lapatinib resistance in HER2+ breast cancer, establishing a SNAI2–PEAK1–INHBA stromal axis.\",\n      \"method\": \"Conditioned medium experiments, PEAK1 knockdown, INHBA depletion, single-cell CycIF imaging, bioinformatic secretome analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditioned medium with target depletion identifies INHBA as necessary factor; single lab\",\n      \"pmids\": [\"34239043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GLI1 transcriptionally upregulates INHBA, and elevated INHBA activates Smad signaling which in turn transcriptionally activates GLI1, forming a positive GLI1/INHBA feedback loop driving gastric cancer progression. Disrupting this interaction inhibits GC tumorigenesis in vivo.\",\n      \"method\": \"Transcriptional reporter assays, gain/loss-of-function, in vivo tumor model, Smad pathway analysis, H. pylori/FTO/YTHDF2/GLI1 m6A pathway analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional feedback loop established with in vivo validation; single lab\",\n      \"pmids\": [\"38676428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAP+ gastric cancer mesenchymal stromal cells secrete INHBA by paracrine signaling, activating SMAD2/3 pathway in gastric cancer cells to increase their proliferation and migration. Additionally, FAP+ GCMSCs induce collagen deposition in ECM, which activates Integrin β1 (ITGB1)→FAK→YAP signaling to promote invasion and stemness.\",\n      \"method\": \"ELISA, Western blot, conditioned medium experiments, flow cytometry-sorted FAP+ GCMSCs, transcriptomic sequencing, IHC, Masson staining\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — paracrine INHBA mechanism defined with SMAD2/3 readout and multiple methods; single lab\",\n      \"pmids\": [\"39615112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-342-3p carried by BMSC-derived extracellular vesicles is transferred into breast cancer cells, downregulating INHBA expression. Reduced INHBA then represses IL13Rα2 expression. This INHBA/IL13Rα2 axis mediates BMSC-EV-induced suppression of breast cancer cell proliferation and metastasis in vitro and in vivo.\",\n      \"method\": \"Co-culture of EVs with MCF-7 cells, luciferase reporter assay, RNA pull-down, RIP assay, nude mouse tumorigenicity assay\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding confirmed by reporter/RIP/pulldown plus in vivo validation; single lab\",\n      \"pmids\": [\"35093789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COL10A1 directly interacts with INHBA (by co-immunoprecipitation) in prostate cancer cells and facilitates PI3K and AKT phosphorylation. INHBA knockdown reverses the oncogenic effects (proliferation, migration, invasion) of COL10A1 overexpression, indicating INHBA is functionally downstream of COL10A1 in this signaling axis.\",\n      \"method\": \"Immunoprecipitation, Western blot for PI3K/AKT phosphorylation, CCK-8, colony formation, Transwell, flow cytometry, rescue experiment in cells and mouse models\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct physical interaction confirmed by Co-IP with functional rescue; single lab\",\n      \"pmids\": [\"39656597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INHBA promotes gemcitabine resistance in pancreatic cancer by binding CTPS1 (cytidine triphosphate synthase 1) and competitively inhibiting SMURF1 (SMAD-specific E3 ubiquitin ligase)-mediated ubiquitination of CTPS1, thereby enhancing CTPS1 stability and promoting pyrimidine metabolism.\",\n      \"method\": \"Immunoprecipitation mass spectrometry, co-IP, ubiquitination assay, drug sensitivity analysis, colony formation, EdU, flow cytometry, xenograft model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — biochemical interaction identified by IP-MS with ubiquitination mechanism validated; single lab\",\n      \"pmids\": [\"41239468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAT8 suppresses vascular senescence by regulating the INHBA/TGF-β/P15 signaling axis. KAT8 deficiency upregulates INHBA and exacerbates aging phenotypes; KAT8 overexpression attenuates vascular senescence. Multi-omics (miRNA-seq, ATAC-seq, RNA-seq) shows hsa-miR-339-3p drives age-related KAT8 downregulation.\",\n      \"method\": \"CRISPR-Cas9 loss/gain-of-function in endothelial cells and mice (C57BL/6J, ApoE-/-), multi-omics (miRNA-seq, ATAC-seq, RNA-seq), vascular senescence phenotyping\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with in vivo CRISPR models, defined INHBA/TGF-β/P15 pathway; single lab\",\n      \"pmids\": [\"41445196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INHBA confers 5-FU chemoresistance in colon cancer cells by facilitating cellular senescence through negative regulation (inactivation) of the Hippo signaling pathway. INHBA downregulation enhances 5-FU sensitivity, reduces senescent cell proportion and IL-6/IL-8 levels; the Hippo inhibitor verteporfin recapitulates INHBA's effects.\",\n      \"method\": \"INHBA knockdown, verteporfin (Hippo inhibitor) treatment, senescence assays (SA-β-gal), cell cycle analysis, xenograft model\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway confirmed with specific inhibitor rescue experiment and in vivo model; single lab\",\n      \"pmids\": [\"38588888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPI1 transcription factor binds the INHBA promoter and transcriptionally activates INHBA expression in gastric cancer cells. INHBA then activates TGF-β signaling to upregulate CCL2, promoting macrophage recruitment and M2 polarization, which in turn facilitates GC cell proliferation, migration, and invasion.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter, siRNA knockdown of INHBA and SPI1, ELISA for CCL2, macrophage polarization assays, in vivo xenograft\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional regulation confirmed by ChIP + reporter assay with functional downstream pathway; single lab\",\n      \"pmids\": [\"40132395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C/EBPβ transcription factor upregulates INHBA expression in gastric cancer. INHBA promotes M2 macrophage polarization and activates the PI3K/AKT pathway, forming a PI3K/AKT/TGF-β positive feedback loop driving tumor progression and metastasis.\",\n      \"method\": \"ChIP, dual-luciferase reporter, CIBERSORT for immune infiltration, INHBA knockdown/overexpression, in vivo mouse model\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional regulation confirmed by ChIP/reporter with in vivo validation and positive feedback loop defined; single lab\",\n      \"pmids\": [\"41540191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Extrasynaptic NMDA receptor (esNMDAR) activation extensively suppresses synaptic activity-regulated transcription including Inhba and Bdnf in hippocampal neurons. In a Huntington's disease mouse model, memantine or FP802 (targeting the NMDAR/TRPM4 complex) restored Inhba and Bdnf expression and attenuated the HD disease marker DARPP-32 loss, placing Inhba as a key neuroprotective gene regulated by the esNMDAR/CREB pathway.\",\n      \"method\": \"Primary hippocampal neuron cultures, pharmacological esNMDAR activation, memantine treatment, FP802 targeting NMDAR/TRPM4, HD mouse model, transcriptomic profiling\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined pathway with in vitro and in vivo disease models; single lab but orthogonal approaches\",\n      \"pmids\": [\"41339520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INHBA promotes gastric cancer progression by targeting ITGA6 (Integrin α6) to activate the MAPK signaling pathway. INHBA and ITGA6 physical interaction was confirmed by Co-IP, and rescue experiments demonstrated that INHBA's pro-tumorigenic effects are mediated through ITGA6/MAPK.\",\n      \"method\": \"RNA-seq, Co-IP, co-immunofluorescence, Western blot, rescue assays, in vivo tumor model, RT-qPCR and IHC in clinical specimens\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction confirmed by Co-IP with pathway rescue experiments and in vivo validation; single lab\",\n      \"pmids\": [\"41799510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Dysregulation of Inhba (elevated basal expression) and Npas4 (superinduction after learning) in DBA/2J mice is associated with altered excitation-inhibition balance in CA1 pyramidal neurons (fewer inhibitory, more excitatory miniature postsynaptic currents), linking Inhba expression levels to synaptic function and cognitive deficits.\",\n      \"method\": \"In vivo spatial object recognition task, IEG expression analysis, whole-cell patch-clamp electrophysiology, primary neuronal cultures\",\n      \"journal\": \"Learning & memory\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlative association between Inhba expression and electrophysiological phenotype; no direct manipulation of Inhba\",\n      \"pmids\": [\"35042829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a PCOS mouse model, Inhba is co-expressed with Smad2 and E2f4 in Lrp2-high thecal cells. siRNA-mediated knockdown of Inhba suppresses thecal cell proliferation in vitro (greatest effect among Inhba, Smad2, E2f4 knockdowns), indicating Inhba acts through Smad2 to drive E2f4-dependent cell cycle entry in thecal hyperplasia.\",\n      \"method\": \"Spatial transcriptomics, siRNA knockdown, EdU incorporation, flow cytometry (cell cycle), DHEA-induced PCOS mouse model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — spatial transcriptomics plus functional siRNA knockdown with defined axis (Inhba/Smad2/E2f4); single lab\",\n      \"pmids\": [\"40831751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mesenchyme-specific deletion of Gata2 reduces Inhba expression in the epididymal mesenchyme, leading to decreased epithelial proliferation and defective epididymal coiling. Dihydrotestosterone supplementation does not rescue the coiling defect, establishing that mesenchymal Gata2 promotes epididymal development through Inhba induction independently of androgen signaling.\",\n      \"method\": \"Conditional Gata2 knockout (mesenchyme-specific), DHT supplementation rescue experiment, epididymal morphometry, Inhba expression analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with hormone rescue exclusion experiment in mouse; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cochlear progenitor cells, TRIM71 represses Inhba and Tgfbr2 expression. Loss of TRIM71 leads to premature Inhba-mediated TGF-β signaling activation, causing early hair cell differentiation. InhbaTgfbr1 double-knockout mice indicate Inhba maintains hair cell progenitors in a proliferative, undifferentiated state by restricting TGF-β-type signaling.\",\n      \"method\": \"Conditional Trim71 KO in mice, Inhba/Tgfbr1 double-KO, transcriptomic profiling of cochlear progenitor cells, hair cell phenotyping, hearing tests\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (double KO) with transcriptomic profiling defines Inhba as TRIM71 target regulating TGF-β pathway; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Integrin α2 (Itgα2) links collagen I engagement to INHBA expression induction in basal-like cancer cells, activating TGF-β signaling which upregulates vimentin while preserving epithelial junction gene expression (partial EMT). Itgα2 also promotes ECM degradation through a TGF-β-independent mechanism, identifying an Itgα2→INHBA→TGFβ axis as a regulator of leader cell function in collective invasion.\",\n      \"method\": \"Collagen I-responsive cell subset identification, Itgα2 manipulation, INHBA expression measurement, TGFβ pathway inhibition, vimentin/junction gene expression analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway induction described but mechanistic details of Itgα2→INHBA link not fully biochemically established; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"INHBA encodes the inhibin βA subunit that homodimerizes to form activin A (or heterodimerizes to form activin AB or inhibin A), and functions primarily as a TGF-β superfamily ligand that signals through SMAD2/3 to regulate cell proliferation, EMT, invasion, fibroblast activation, macrophage polarization, immune suppression (via PD-L1 and IFN-γ pathway suppression), and neuroprotection (via nuclear calcium-driven transcription downstream of synaptic NMDA receptors); its mRNA stability is post-transcriptionally regulated by RNA-binding proteins (IGF2BP1, HuR) and miRNAs, while its transcription is regulated by factors including SPI1, C/EBPβ, BHLHE40, and GLI1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"INHBA encodes the inhibin βA subunit, which homodimerizes to form activin A, a secreted TGF-β superfamily ligand that signals through SMAD2/3 to regulate cell proliferation, epithelial-mesenchymal transition, fibroblast activation, macrophage polarization, and immune evasion across diverse tissue contexts [PMID:10932194, PMID:30963572, PMID:31827640, PMID:38360876]. Activin A drives cancer-associated fibroblast activation via paracrine SMAD2 signaling, induces PD-L1 expression on fibroblasts, promotes Treg differentiation, and suppresses IFN-γ-dependent CD8+ T cell recruitment through downregulation of CXCL9/CXCL10, thereby shaping an immunosuppressive tumor microenvironment [PMID:28814667, PMID:38360876, PMID:39223366]. In neurons, nuclear calcium signaling downstream of synaptic NMDA receptors transcriptionally induces INHBA, and the resulting activin A reduces extrasynaptic NMDA receptor-mediated calcium influx to confer neuroprotection against excitotoxicity and ischemic injury [PMID:26279570, PMID:41339520]. INHBA mRNA stability is post-transcriptionally regulated by IGF2BP1 in an m6A-dependent manner and by HuR, while its transcription is controlled by SPI1, C/EBPβ, GLI1, and KAT8, and it is repressed by multiple miRNAs including miR-146a, miR-211, miR-130b-3p, and miR-342-3p [PMID:37644505, PMID:35338119, PMID:27541693, PMID:40132395, PMID:41540191].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Knock-in of Inhbb into the Inhba locus demonstrated that most Inhba-null phenotypes (craniofacial defects) arise from spatial/temporal expression differences rather than ligand-receptor specificity, while also revealing activin A-specific roles in somatic and gonadal tissues that Inhbb cannot substitute.\",\n      \"evidence\": \"Gene knock-in rescue in mice with dosage analysis\",\n      \"pmids\": [\"10932194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of activin A-specific (non-rescuable) functions undefined\", \"Receptor-level selectivity versus co-receptor usage not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Activin A was established as a proliferative signal in epithelial cancer cells, with INHBA expression shown to be epigenetically regulated through promoter methylation and histone acetylation, providing the first mechanistic link between epigenetic derepression and activin-driven tumor growth.\",\n      \"evidence\": \"Exogenous activin A, follistatin inhibition, INHBA siRNA, and 5-AZA/TSA treatment in esophageal adenocarcinoma cells\",\n      \"pmids\": [\"19240652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific histone marks and demethylases at INHBA promoter not identified\", \"In vivo validation of epigenetic regulation lacking\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A neuroprotective circuit was delineated in which BDNF-activated synaptic NMDA receptors trigger nuclear calcium signaling to induce INHBA transcription, and the resulting activin A attenuates extrasynaptic NMDA receptor calcium influx, protecting neurons from excitotoxicity and ischemic injury.\",\n      \"evidence\": \"Nuclear calcium blockade, Inhba siRNA, recombinant activin A rescue, calcium imaging, mouse stroke model\",\n      \"pmids\": [\"26279570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which activin A reduces extrasynaptic NMDA receptor activity not defined at the molecular level\", \"Downstream transcriptional targets in neurons not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"INHBA was placed as a downstream effector of miR-146a in macrophage polarization, showing that activin A promotes M1 and suppresses M2 macrophage markers — the first direct evidence for INHBA controlling innate immune cell phenotype via a specific miRNA regulatory input.\",\n      \"evidence\": \"3′-UTR luciferase reporter, miR-146a overexpression/knockdown, INHBA rescue in macrophages\",\n      \"pmids\": [\"27541693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway downstream of INHBA in macrophage polarization not specified\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"INHBA was identified as a key paracrine mediator linking adrenergic stress to cancer-associated fibroblast activation, establishing the concept that tumor cell-derived activin A remodels the stroma.\",\n      \"evidence\": \"Restraint-stress model, β-blocker treatment, INHBA ablation in ovarian cancer in vitro and in vivo\",\n      \"pmids\": [\"28814667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adrenergic receptor subtype and transcriptional pathway leading to INHBA induction not defined\", \"Whether fibroblast activation is SMAD-dependent not tested in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SMAD2 was identified as the required downstream effector of INHBA-mediated fibroblast activation in ovarian cancer, and INHBA knockdown in gastric cancer confirmed TGF-β pathway dependence for proliferation, migration, and invasion, solidifying SMAD2/3 as the canonical intracellular pathway for activin A's pro-tumorigenic effects.\",\n      \"evidence\": \"INHBA knockdown, Smad2 pathway inhibition, tumor xenografts in gastric and ovarian cancer\",\n      \"pmids\": [\"31827640\", \"30963572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-SMAD signaling contributions (e.g., MAPK, PI3K) not excluded\", \"Identity of activin receptor complexes on fibroblasts not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"miR-211 was shown to directly repress INHBA, and its loss led to enhanced TGF-β/Smad2/3 activation and cancer stemness in prostate cancer, adding a second miRNA regulatory axis and linking INHBA to stem cell properties.\",\n      \"evidence\": \"miR-211 overexpression/knockdown, INHBA siRNA, sphere-forming assay, in vivo tumor model\",\n      \"pmids\": [\"33223523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which INHBA/activin A promotes stemness transcription factors unknown\", \"Interaction with androgen receptor signaling not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"INHBA was demonstrated to induce EMT in breast cancer and to be a necessary factor in PEAK1+ mesenchymal stromal cell conditioned medium conferring lapatinib resistance, establishing activin A as a mediator of both intrinsic motility programs and therapy resistance through stromal interactions.\",\n      \"evidence\": \"INHBA overexpression/silencing for EMT markers; conditioned medium depletion identifying INHBA as required for PEAK1-mediated lapatinib resistance; metabolic profiling showing glycolysis dependence\",\n      \"pmids\": [\"34346300\", \"34239043\", \"35248133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor engagement on cancer cells not shown\", \"Whether EMT and drug resistance share the same SMAD pathway branch unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Post-transcriptional regulation of INHBA mRNA was mechanistically defined: circTHBS1 sponges miR-204-5p to de-repress INHBA, and additionally recruits HuR to stabilize INHBA mRNA, connecting non-coding RNA networks to INHBA-driven TGF-β activation in gastric cancer. Separately, metformin was shown to suppress INHBA to block PI3K/Akt/cyclin D1 and induce G1/S arrest in colorectal cancer.\",\n      \"evidence\": \"RNA pull-down, RIP, luciferase reporter for circTHBS1/miR-204-5p/HuR axis; INHBA knockdown/overexpression with metformin and cell cycle analysis\",\n      \"pmids\": [\"35338119\", \"35236827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HuR binding is m6A-dependent or independent not resolved\", \"Metformin's direct target leading to INHBA suppression not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"IGF2BP1 was identified as an m6A-dependent stabilizer of INHBA mRNA that cooperates with G3BP1, directly linking epitranscriptomic regulation to INHBA protein output and Smad2/3-driven invasion in esophageal squamous cell carcinoma. Separately, a miR-130b-3p/INHBA/IL-8 axis was shown to control angiogenesis in diabetic ischemia.\",\n      \"evidence\": \"RIP-seq, RNA pulldown, m6A-specific PCR, BTYNB inhibitor for IGF2BP1; miR-130b mimic in vivo in ischemic limb model\",\n      \"pmids\": [\"37644505\", \"37097749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific m6A writer depositing marks on INHBA mRNA not identified\", \"Whether IGF2BP1 and HuR compete or cooperate on INHBA mRNA unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"INHBA's immunoregulatory functions were resolved at two levels: in cancer-associated fibroblasts, activin A induces autocrine PD-L1 via SMAD2 and promotes Treg differentiation through cell contact; in tumor cells, INHBA suppresses IFN-γ signaling to reduce CXCL9/CXCL10 and impair CD8+ T cell infiltration, explaining resistance to anti-PD-L1 therapy that is reversible by activin A neutralization.\",\n      \"evidence\": \"INHBA knockdown in CAFs, T cell co-culture, anti-activin A antibody in vivo, spatial transcriptomics; Inhba gain/loss-of-function across four syngeneic tumor models with IFN-γ pathway analysis\",\n      \"pmids\": [\"38360876\", \"39223366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SMAD2-dependent PD-L1 induction and IFN-γ suppression are the same or distinct mechanisms is unresolved\", \"Activin receptor expression pattern across immune cell subsets not characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Transcriptional regulation of INHBA was mapped: GLI1 directly activates INHBA transcription, and Smad-mediated feedback transcriptionally reactivates GLI1, creating a positive feedback loop in gastric cancer; FAP+ mesenchymal stromal cells secrete INHBA to activate SMAD2/3 in neighboring cancer cells.\",\n      \"evidence\": \"ChIP and reporter assays for GLI1; ELISA and conditioned medium with FAP+ sorted stromal cells; in vivo gastric cancer models\",\n      \"pmids\": [\"38676428\", \"39615112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the GLI1/INHBA feedback loop is initiated and terminated not defined\", \"Relative contribution of stromal vs. tumor-intrinsic INHBA unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple transcriptional inputs to INHBA were confirmed: SPI1 binds the INHBA promoter to drive CCL2-mediated macrophage recruitment, and C/EBPβ activates INHBA to establish a PI3K/AKT/TGF-β positive feedback loop, while KAT8 deficiency de-represses INHBA contributing to vascular senescence through TGF-β/P15 signaling.\",\n      \"evidence\": \"ChIP and dual-luciferase reporters for SPI1 and C/EBPβ; CRISPR KAT8 KO with multi-omics in endothelial cells and mice\",\n      \"pmids\": [\"40132395\", \"41540191\", \"41445196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How multiple transcription factors (SPI1, C/EBPβ, GLI1, KAT8) are hierarchically organized at the INHBA promoter is unknown\", \"Chromatin state and enhancer architecture at the INHBA locus not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A non-canonical intracellular function for INHBA protein was uncovered: INHBA binds CTPS1 and competitively inhibits SMURF1-mediated ubiquitination of CTPS1, stabilizing it to enhance pyrimidine metabolism and gemcitabine resistance in pancreatic cancer. Additionally, INHBA binds ITGA6 to activate MAPK signaling in gastric cancer, and interacts with COL10A1 to activate PI3K/AKT in prostate cancer.\",\n      \"evidence\": \"IP-mass spectrometry, co-IP, ubiquitination assay, BTYNB for CTPS1 axis; co-IP and rescue for ITGA6/MAPK and COL10A1/PI3K/AKT\",\n      \"pmids\": [\"41239468\", \"41799510\", \"39656597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether INHBA–CTPS1 interaction occurs intracellularly or extracellularly is unclear\", \"INHBA interaction with ITGA6 and COL10A1 each shown by single-lab co-IP without reciprocal or structural validation\", \"Relationship between these non-canonical interactions and classical activin receptor signaling not clarified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extrasynaptic NMDA receptor activation suppresses Inhba transcription in hippocampal neurons, and pharmacological restoration (memantine, FP802) of Inhba expression attenuated neurodegeneration in a Huntington's disease mouse model, extending the neuroprotective role of INHBA beyond ischemia to chronic neurodegeneration.\",\n      \"evidence\": \"Pharmacological esNMDAR activation, memantine and FP802 treatment, HD mouse model, transcriptomic profiling\",\n      \"pmids\": [\"41339520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether activin A protein levels and secretion are restored in vivo not measured\", \"Downstream neuroprotective effectors of activin A in HD context not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of activin A interactions with non-canonical partners (CTPS1, ITGA6, COL10A1); how multiple transcription factors and post-transcriptional regulators are integrated at the INHBA locus in different cell types; the relative contributions of autocrine versus paracrine activin A signaling in the tumor microenvironment; and whether the intracellular/non-canonical functions of INHBA protein are independent of its secreted ligand role.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data for INHBA interactions with CTPS1, ITGA6, or COL10A1\", \"Relative autocrine vs. paracrine contribution of INHBA in tumors not quantified\", \"Whether intracellular INHBA functions require dimerization is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6, 10, 11, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [21, 23]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 8, 14, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 4, 10, 11, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0000000\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6, 8, 9, 10, 11, 12, 17, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 10, 11, 24, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 8, 14, 21, 23]}\n    ],\n    \"complexes\": [\n      \"Activin A (βA homodimer)\",\n      \"Activin AB (βA/βB heterodimer)\",\n      \"Inhibin A (α/βA heterodimer)\"\n    ],\n    \"partners\": [\n      \"SMAD2\",\n      \"SMAD3\",\n      \"IGF2BP1\",\n      \"G3BP1\",\n      \"CTPS1\",\n      \"COL10A1\",\n      \"ITGA6\",\n      \"ELAVL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}