{"gene":"INHBA","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2000,"finding":"Replacement of the Inhba mature-protein coding region with Inhbb (creating the InhbaBK knock-in allele) rescued the craniofacial/palate/tooth phenotypes of Inhba-null mice but produced novel somatic, testicular, genital, and hair-growth phenotypes, demonstrating that functional compensation within the TGF-β superfamily depends on appropriate spatiotemporal expression and that Inhba and Inhbb have overlapping but non-identical in vivo activities.","method":"Gene knock-in / targeted replacement (Inhba locus replaced with Inhbb coding sequence), in vivo mouse genetics, phenotypic rescue analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vivo reconstitution with allelic replacement, rigorous genetic rescue experiment, replicated across multiple phenotypic endpoints","pmids":["10932194"],"is_preprint":false},{"year":2015,"finding":"BDNF activates synaptic NMDA receptors, triggering nuclear calcium signaling that transcriptionally upregulates inhba (inhibin β-A/activin A homodimer). The resulting activin A then reduces extrasynaptic NMDA-receptor-mediated calcium influx, thereby protecting neurons against mitochondrial dysfunction and excitotoxicity. This BDNF → synaptic NMDAR → nuclear calcium → Inhba → reduced extrasynaptic NMDAR signaling axis confers neuroprotection against ischemic brain damage in a mouse stroke model.","method":"Primary neuron live-cell calcium imaging, pharmacological block of synaptic vs. extrasynaptic NMDARs, siRNA knockdown of inhba, recombinant activin A application, in vivo mouse stroke model, nuclear calcium reporters","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, pharmacology, KD, recombinant protein, in vivo model), causal pathway established with specific readouts","pmids":["26279570"],"is_preprint":false},{"year":2009,"finding":"INHBA overexpression in esophageal adenocarcinoma (EAC) cell lines promotes cell proliferation; exogenous activin A increases proliferation of FLO and OE-33 cells, while follistatin (activin inhibitor) and INHBA-targeting siRNA reduce proliferation. INHBA expression in EAC cell lines is upregulated by treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine and the HDAC inhibitor trichostatin A, indicating that promoter demethylation and histone acetylation regulate INHBA expression.","method":"siRNA knockdown, exogenous recombinant activin A treatment, follistatin inhibitor treatment, 5-AZA and trichostatin A epigenetic drug treatment, cell proliferation assays, real-time RT-PCR, IHC","journal":"Journal of thoracic oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (gain/loss-of-function, inhibitor, epigenetic drug) in single lab, two orthogonal mechanistic approaches","pmids":["19240652"],"is_preprint":false},{"year":2017,"finding":"Cancer-cell-derived INHBA (inhibin β-A/activin A) induces cancer-associated fibroblast (CAF) activation in ovarian cancer models. Adrenergic (stress) signaling increases INHBA production by cancer cells; ablating INHBA expression decreases CAF phenotype and associated collagen/ECM deposition both in vitro and in vivo. This identifies INHBA as a paracrine driver of the CAF phenotype downstream of adrenergic signaling.","method":"In vivo restraint-stress mouse models of ovarian/breast/colon cancer, β-blocker pharmacology, bioinformatics-guided systems biology, siRNA/shRNA ablation of INHBA in vitro and in vivo, immunofluorescence/IHC for CAF markers and collagens","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cancer models, in vivo and in vitro validation, pharmacological and genetic perturbation of INHBA, consistent results across systems","pmids":["28814667"],"is_preprint":false},{"year":2016,"finding":"miR-146a directly targets the 3'-UTR of INHBA to suppress its expression. INHBA mediates macrophage M1/M2 polarization: INHBA overexpression rescues M1 cytokine production (IL-6, IL-12, TNF-α) suppressed by miR-146a, and rescues M2 markers (Arg1, CCL17, CCL22) suppressed by miR-146a inhibition. Thus miR-146a regulates monocyte polarization through INHBA.","method":"3'-UTR luciferase reporter assay, miRNA overexpression/knockdown, INHBA overexpression/knockdown rescue experiments, cytokine measurement, flow cytometry for macrophage polarization markers","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct 3'-UTR binding validated by luciferase assay, epistatic rescue experiments establish INHBA as functional downstream target, multiple orthogonal methods","pmids":["27541693"],"is_preprint":false},{"year":2019,"finding":"INHBA knockdown in ovarian cancer cells impairs xenograft tumor growth in vivo by reducing stromal fibroblast activation. Mechanistically, INHBA-induced stromal fibroblast activation depends on Smad2 signaling; inhibiting Smad2 pathway reverses INHBA-driven fibroblast activation.","method":"shRNA knockdown of INHBA in OC cells, xenograft mouse model, Smad2 pathway inhibition, in vitro co-culture fibroblast activation assays","journal":"Disease markers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft plus Smad2 inhibitor rescue; single lab but two orthogonal approaches (genetic KD + pharmacological inhibition)","pmids":["31827640"],"is_preprint":false},{"year":2019,"finding":"INHBA gene silencing via shRNA inhibits TGF-β signaling pathway activation in gastric cancer cells, reducing cell migration, invasion, proliferation, and tumor growth in a xenograft nude mouse model. Conversely, INHBA is required to maintain active TGF-β signaling in GC cells.","method":"shRNA knockdown of INHBA, Western blot for TGF-β pathway proteins, migration/invasion/proliferation assays, xenograft tumor model in nude mice","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vitro and in vivo with defined pathway readout; single lab","pmids":["30963572"],"is_preprint":false},{"year":2021,"finding":"INHBA in ovarian CAFs induces PD-L1 expression in an autocrine manner through SMAD2-dependent signaling, and INHBA+ CAFs promote regulatory T cell (Treg) differentiation via direct cell contact. Neutralizing Activin A (INHBA homodimer) antibody in vivo attenuates tumor progression and reduces pro-tumorigenic myofibroblasts and macrophages.","method":"INHBA knockdown in human ovarian CAFs, T cell/CAF co-culture assay for Treg differentiation, recombinant Activin A treatment, anti-Activin A neutralizing antibody in vivo in mouse ovarian cancer models, SMAD2 pathway analysis, spatiotemporal patient tissue analysis","journal":"NPJ precision oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KD, recombinant protein, neutralizing antibody in vivo), mechanistic pathway (INHBA→SMAD2→PD-L1) and cellular consequence (Treg differentiation) both established, patient tissue validation","pmids":["38360876"],"is_preprint":false},{"year":2021,"finding":"INHBA promotes colon cancer cell proliferation, migration, and invasion through upregulation of versican (VCAN). The INHBA-VCAN correlation was verified by immunoprecipitation, and INHBA interference inhibited aggressive behavior by downregulating VCAN.","method":"Immunoprecipitation, siRNA knockdown of INHBA and VCAN, overexpression, CCK-8/colony formation, wound healing, Transwell assays","journal":"The Journal of international medical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP to establish INHBA-VCAN relationship, single lab, limited mechanistic follow-up on how INHBA regulates VCAN","pmids":["34130530"],"is_preprint":false},{"year":2021,"finding":"In HER2+ basal breast cancer cells, INHBA knockdown slows growth, increases lapatinib sensitivity, and shifts cellular metabolism from glycolysis to oxidative phosphorylation, indicating INHBA supports a glycolytic and invasive phenotype in the basal subtype.","method":"siRNA knockdown screen, 2D and 3D cell culture validation, metabolic profiling, lapatinib sensitivity assays","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal readouts (growth, drug sensitivity, metabolomics) in multiple cell lines; single lab","pmids":["35248133"],"is_preprint":false},{"year":2021,"finding":"MSC-derived INHBA/activin-A is a necessary paracrine factor mediating lapatinib resistance of HER2+ breast cancer cells in a PEAK1-dependent stromal axis (SNAI2-PEAK1-INHBA). INHBA in conditioned media from PEAK1-expressing MSCs promotes lapatinib resistance, as established by analysis of PEAK1-dependent secreted factors.","method":"Conditioned medium transfer experiments, PEAK1 knockdown/overexpression in MSCs and CAFs, secretome analysis, single-cell cyclic immunofluorescence (CycIF), co-culture systems","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — INHBA identified as necessary secreted factor by conditioned media analysis and genetic perturbation; single lab, multiple orthogonal approaches","pmids":["34239043"],"is_preprint":false},{"year":2022,"finding":"Metformin suppresses CRC cell proliferation causing G1/S arrest by downregulating INHBA expression, which blocks TGF-β signaling activation and downstream PI3K/Akt pathway activity, leading to reduced cyclin D1.","method":"INHBA knockdown and overexpression in CRC cells, metformin treatment, cell cycle analysis (flow cytometry), Western blot for TGF-β/PI3K/Akt pathway components, proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function with defined pathway readout; single lab, two orthogonal perturbations (genetic + pharmacological)","pmids":["35236827"],"is_preprint":false},{"year":2022,"finding":"CircTHBS1 promotes INHBA expression via two mechanisms: (1) sponging miR-204-5p to relieve repression of INHBA mRNA, and (2) enhancing HuR-mediated mRNA stability of INHBA. Elevated INHBA consequently activates the TGF-β pathway to drive gastric cancer malignancy.","method":"RNA pulldown, luciferase reporter assay, RNA immunoprecipitation (RIP), gain/loss-of-function assays in vitro and in vivo, transcriptome analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two distinct RNA-level mechanisms validated by RIP and luciferase assays; single lab, multiple orthogonal methods","pmids":["35338119"],"is_preprint":false},{"year":2023,"finding":"RNA-binding protein IGF2BP1 binds and stabilizes INHBA mRNA (via m6A-dependent mechanism), leading to higher INHBA protein expression and activation of Smad2/3 signaling, which promotes invasion and migration of esophageal squamous cancer cells. IGF2BP1 also interacts with G3BP1, and G3BP1 knockdown similarly downregulates INHBA-Smad2/3 signaling.","method":"RNA immunoprecipitation sequencing (RIP-seq), RNA pulldown, gene-specific m6A PCR, RNA stability assays, immunofluorescence, mass spectrometry, siRNA knockdown, in vivo metastasis assays, small-molecule inhibitor BTYNB","journal":"Experimental hematology & oncology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct RNA-binding established by RIP-seq and pulldown, m6A-dependent stabilization mechanism confirmed, downstream Smad2/3 signaling validated, multiple orthogonal methods in single study","pmids":["37644505"],"is_preprint":false},{"year":2023,"finding":"miR-130b-3p directly targets and represses INHBA mRNA. INHBA repression (either by miR-130b overexpression or INHBA siRNA) induces IL-8 expression, a pro-angiogenic chemokine, and improves revascularization in diabetic ischemic limbs in vivo. Thus a miR-130b/INHBA axis controls angiogenesis by modulating BMP/TGF-β signaling in endothelial cells.","method":"miRNA target prediction with experimental validation, miRNA mimic/inhibitor transfection in endothelial cells, siRNA knockdown of INHBA, in vitro angiogenic assays (proliferation, migration, sprouting), in vivo femoral artery ligation in diabetic (db/db) mice, RNA-seq/GSEA","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct targeting validated, INHBA siRNA recapitulates miR-130b phenotype (epistasis), in vivo validation in disease model, multiple orthogonal methods","pmids":["37097749"],"is_preprint":false},{"year":2024,"finding":"Tumor-intrinsic INHBA suppresses the IFN-γ signaling pathway, leading to (1) reduced IFN-γ-induced PD-L1 expression (causing poor response to anti-PD-L1 therapy) and (2) decreased secretion of IFN-γ-stimulated chemokines CXCL9 and CXCL10, impairing effector T cell infiltration into tumors. Activin A-specific antibody garetosmab improves anti-tumor immunity and synergizes with anti-PD-L1 antibody atezolizumab.","method":"INHBA gain/loss-of-function in CT26, MC38, B16, and 4T1 mouse tumor models, anti-PD-L1 antibody treatment, anti-Activin A antibody (garetosmab) treatment, flow cytometry for T cell infiltration, IFN-γ signaling pathway analysis, cytokine/chemokine measurement","journal":"Acta pharmacologica Sinica","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo tumor models, genetic gain/loss-of-function, pharmacological neutralization, mechanistic pathway (INHBA→IFN-γ suppression→CXCL9/10 reduction→T cell exclusion) established with multiple readouts","pmids":["39223366"],"is_preprint":false},{"year":2024,"finding":"KAT8 (lysine acetyltransferase 8) suppresses vascular senescence by epigenetically regulating the INHBA/TGF-β/P15 signaling axis. KAT8 deficiency increases INHBA expression, promoting TGF-β-mediated senescence, while KAT8 overexpression attenuates vascular senescence. hsa-miR-339-3p is identified as responsible for age-related KAT8 downregulation upstream of this axis.","method":"CRISPR-Cas9 loss-of-function and gain-of-function in endothelial cells and mice (C57BL/6J and ApoE-/-), integrated miRNA-seq/ATAC-seq/RNA-seq multi-omics analysis, senescence assays","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics plus genetic perturbation in vitro and in vivo; INHBA identified as downstream target of KAT8 within this axis; single lab","pmids":["41445196"],"is_preprint":false},{"year":2024,"finding":"GLI1 (Hedgehog transcription factor) transcriptionally upregulates INHBA in gastric cancer. Elevated INHBA in turn activates Smads signaling, which transcriptionally activates GLI1, forming a positive GLI1/INHBA feedback loop that drives GC tumorigenesis. Additionally, H. pylori upregulates GLI1 via m6A modification through the FTO/YTHDF2/GLI1 pathway, feeding into this loop.","method":"Chromatin immunoprecipitation, reporter assays, gain/loss-of-function for GLI1 and INHBA, in vivo mouse tumor models disrupting GLI1-INHBA interaction, m6A modification analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays establish transcriptional regulation; epistatic feedback loop demonstrated in vivo; single lab","pmids":["38676428"],"is_preprint":false},{"year":2024,"finding":"INHBA promotes chemoresistance in pancreatic cancer by physically interacting with CTPS1 (cytidine triphosphate synthase 1) and competitively inhibiting SMURF1-mediated ubiquitination of CTPS1, thereby stabilizing CTPS1 protein and enhancing pyrimidine metabolism that supports gemcitabine resistance.","method":"Immunoprecipitation mass spectrometry (to identify CTPS1 as binding partner), co-immunoprecipitation, ubiquitination assays, drug sensitivity analysis, xenograft mouse model, EdU/flow cytometry/colony formation assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding partner identified by IP-MS and validated by co-IP; ubiquitination mechanism established; single lab with multiple orthogonal approaches","pmids":["41239468"],"is_preprint":false},{"year":2024,"finding":"FAP+ gastric cancer mesenchymal stromal cells secrete INHBA via paracrine signaling to activate SMAD2/3 signaling in gastric cancer cells, increasing their proliferation and migration. These cells also induce collagen deposition that acts via integrin ITGB1 to phosphorylate FAK and YAP, promoting invasion and stemness.","method":"FAP+ cell isolation by flow cytometry, conditioned medium/ELISA experiments, Western blot for SMAD2/3, Masson's trichrome staining, IHC, transcriptomic sequencing","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — paracrine INHBA secretion measured by ELISA, downstream SMAD2/3 activation by Western blot, mechanistic pathway established; single lab","pmids":["39615112"],"is_preprint":false},{"year":2024,"finding":"INHBA promotes gastric cancer progression by interacting with ITGA6 (integrin alpha-6) to activate the MAPK signaling pathway. Co-immunoprecipitation and co-immunofluorescence confirmed the INHBA-ITGA6 interaction; rescue experiments demonstrated that ITGA6 mediates INHBA-driven MAPK activation, proliferation, migration, and invasion.","method":"Co-immunoprecipitation (Co-IP), co-immunofluorescence, RNA-seq pathway analysis, Western blot, rescue experiments with ITGA6 manipulation, in vivo xenograft models, RT-qPCR, IHC","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct INHBA-ITGA6 interaction validated by reciprocal Co-IP and Co-IF; rescue experiments support epistatic relationship; single lab","pmids":["41799510"],"is_preprint":false},{"year":2022,"finding":"INHBA confers 5-FU chemoresistance in colon cancer by promoting cellular senescence and inactivating the Hippo signaling pathway (as validated using the Hippo pathway inhibitor Verteporfin). INHBA knockdown enhanced 5-FU sensitivity, inhibited proliferation, promoted apoptosis, and reduced senescent cell proportion and senescence markers (IL-6, IL-8).","method":"INHBA knockdown/overexpression, 5-FU drug sensitivity assays, cellular senescence assays (SA-β-gal, senescence marker expression), Verteporfin (Hippo inhibitor) treatment, in vivo xenograft model, flow cytometry for cell cycle","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic perturbation combined with pathway-specific pharmacological inhibitor (Verteporfin) establishes Hippo pathway involvement; in vivo validation; single lab","pmids":["38588888"],"is_preprint":false},{"year":2025,"finding":"Extrasynaptic NMDA receptor (esNMDAR) activation suppresses Inhba transcription in hippocampal neurons as part of a broad neurodegenerative transcriptional dysregulation program. In a Huntington's disease mouse model, treatment with memantine or FP802 (NMDAR/TRPM4 complex inhibitor) restores Inhba expression along with Bdnf and Homer1, attenuating disease progression markers. Inhba is identified as a major neuroprotective gene whose suppression contributes to neurodegeneration.","method":"Primary hippocampal neuron cultures with pharmacological esNMDAR activation, RNA-seq, Huntington's disease mouse model (memantine and FP802 treatment), quantitative gene expression analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro neuronal model and in vivo HD mouse model with pharmacological rescue; Inhba identified as key downstream target; single lab, multiple models","pmids":["41339520"],"is_preprint":false},{"year":2021,"finding":"INHBA transfection in sheep granulosa cells: overexpression significantly decreases activin A and estradiol secretion while increasing inhibin A and progesterone secretion. INHBA overexpression also decreased FSH-β subunit expression. INHBA knockdown inhibited expression of multiple TGF-β-related genes. These results establish INHBA as a regulator of granulosa cell hormone synthesis and follicular development.","method":"In vitro transfection (overexpression and siRNA knockdown) in sheep granulosa cells, hormone ELISA, RT-qPCR/Western blot for cell cycle and apoptosis genes, proliferation assays","journal":"Theriogenology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional perturbation (OE and KD) with multiple hormonal readouts; single lab, clean functional phenotype","pmids":["34537472"],"is_preprint":false},{"year":2025,"finding":"Spatial transcriptomics in a PCOS mouse model identified an Inhba/Smad2/E2f4 signaling axis as a key regulator of Lrp2-high thecal cell proliferation. Knockdown of any component of this axis (Inhba, Smad2, or E2f4) significantly suppressed thecal cell proliferation in vitro, with the greatest effect from Inhba silencing. This axis is implicated in androgen excess in PCOS.","method":"Spatial transcriptomics, siRNA knockdown of Inhba/Smad2/E2f4, EdU incorporation assay, flow cytometry for cell cycle, DHEA-induced PCOS mouse model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — spatial transcriptomics plus functional validation by siRNA knockdown with cell cycle readout; single lab","pmids":["40831751"],"is_preprint":false},{"year":2025,"finding":"In a preprint, integrin α2 (Itgα2) engagement with collagen I induces INHBA expression in basal-like breast cancer cells, activating TGF-β signaling which upregulates vimentin while preserving epithelial junction gene expression, thus driving a partial EMT (leader cell phenotype) that enables collective invasion. Itgα2 also promotes ECM degradation through a TGF-β-independent mechanism.","method":"Collagen I-responsive cell subset identification, Itgα2 perturbation, INHBA expression analysis, TGF-β signaling readouts, vimentin and E-cadherin/junction gene quantification, in vitro collective invasion assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, mechanistic pathway proposed with supporting cell biology data but not yet peer-reviewed; limited mechanistic depth on how Itgα2 induces INHBA","pmids":[],"is_preprint":true},{"year":2025,"finding":"In a preprint, TRIM71 represses Inhba (and Tgfbr2) expression in cochlear progenitor cells. Loss of TRIM71 function leads to premature hair cell differentiation; analysis of Inhba;Tgfbr1 double knockout mice indicates TRIM71 maintains hair cell progenitors in a proliferative undifferentiated state by restricting TGF-β-type signaling, placing Inhba downstream of TRIM71 in this developmental pathway.","method":"Conditional Trim71 knockout mice, Inhba;Tgfbr1 double knockout mice, transcriptomic profiling of cochlear progenitors, in vivo developmental timing analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — double knockout genetic epistasis in mouse development; preprint, single lab; places Inhba in TGF-β pathway downstream of TRIM71 but requires peer review","pmids":[],"is_preprint":true},{"year":2025,"finding":"In a preprint, mesenchyme-specific deletion of Gata2 reduces Inhba expression in the epididymal mesenchyme and impairs epithelial proliferation and epididymal coiling. This identifies Inhba as downstream of GATA2 in androgen-independent mesenchymal signaling required for epididymal development.","method":"Conditional mesenchyme-specific Gata2 knockout mice, dihydrotestosterone supplementation rescue experiments, Inhba expression analysis by RT-qPCR/IHC, epithelial proliferation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function with defined phenotype; preprint, single lab; Inhba placed downstream of GATA2 but not directly validated with Inhba rescue","pmids":[],"is_preprint":true},{"year":2025,"finding":"In JunB-deficient Th17 cells, Inhba (encoding activin A) is identified as a JunB transcriptional target. Supplementation with recombinant activin A restores IL-17A and Rorc expression during pathogenic Th17 cell differentiation in JunB-deficient conditions, establishing activin A as a functional downstream effector of JunB-driven Th17 differentiation.","method":"dTAG protein degradation of JunB in Th17 cells, transcriptomic analysis, recombinant activin A rescue, flow cytometry for IL-17A and RORγt, in vitro and in vivo Th17 differentiation","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — functional rescue with recombinant activin A supports INHBA as JunB target; preprint, single lab","pmids":[],"is_preprint":true},{"year":2022,"finding":"INHBA transcription in colon cancer cells is directly activated by the transcription factor BHLHE40, as established through database analysis and experimental validation showing BHLHE40 modulates INHBA expression; BHLHE40 knockdown suppresses INHBA and reduces colon cancer cell proliferation and migration.","method":"siRNA knockdown of BHLHE40, Western blot and RT-qPCR, database analysis (JASPAR, PROMO, ENCODE), CCK-8 proliferation and wound healing assays","journal":"Journal of clinical laboratory analysis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcription factor-target relationship inferred from database prediction and knockdown; no direct promoter binding assay (e.g., ChIP) performed; single lab","pmids":["35689549"],"is_preprint":false},{"year":2025,"finding":"SPI1 (PU.1) transcription factor binds to the INHBA promoter and transcriptionally activates INHBA expression in gastric cancer cells. INHBA in turn activates TGF-β signaling to upregulate CCL2, which promotes macrophage recruitment and M2 polarization, facilitating GC cell proliferation, migration, and invasion.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), Western blot for TGF-β pathway, macrophage recruitment assays, co-culture experiments, in vivo xenograft model","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding validated by ChIP and luciferase reporter; downstream TGF-β/CCL2 pathway established; single lab","pmids":["40132395"],"is_preprint":false},{"year":2026,"finding":"COL10A1 directly interacts with INHBA (co-immunoprecipitation) and facilitates PI3K/AKT pathway phosphorylation in prostate cancer cells and mouse models. INHBA knockdown reverses the oncogenic effects of COL10A1 overexpression, establishing INHBA as a required downstream mediator of COL10A1-driven PI3K/AKT signaling and PCa progression.","method":"Co-immunoprecipitation (Co-IP), Western blot for PI3K/AKT phosphorylation, siRNA knockdown of INHBA (rescue experiment), CCK-8, colony formation, flow cytometry, Transwell, wound-healing assays, mouse models","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction by Co-IP with functional rescue; PI3K/AKT signaling readout; single lab","pmids":["39656597"],"is_preprint":false},{"year":2026,"finding":"THBS2 directly interacts with INHBA to activate the FAK/PI3K/AKT signaling pathway in prostate cancer. INHBA knockdown reverses the oncogenic effects of THBS2 overexpression, demonstrating epistatic dependence of THBS2-driven signaling on INHBA.","method":"STRING interaction prediction, Western blot for FAK/PI3K/AKT phosphorylation, INHBA knockdown rescue experiments, overexpression/knockdown functional assays (CCK-8, invasion, EMT markers)","journal":"Analytical cellular pathology (Amsterdam)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction inferred from STRING and Western blot pathway analysis without direct Co-IP validation; single lab","pmids":["41810913"],"is_preprint":false},{"year":2026,"finding":"C/EBPβ transcriptionally upregulates INHBA in gastric cancer cells (validated by dual-luciferase reporter and ChIP). INHBA then induces M2 macrophage polarization and activates a PI3K/AKT/TGF-β positive feedback loop, promoting tumor metastasis and growth.","method":"Dual-luciferase reporter assay, ChIP, INHBA gain/loss-of-function, macrophage polarization co-culture assays (CIBERSORT), in vitro/in vivo tumor models","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding validated by ChIP and reporter; macrophage polarization and PI3K/AKT axis established; single lab","pmids":["41540191"],"is_preprint":false},{"year":2026,"finding":"INHBA silencing in valvular interstitial cells (VICs) reduces osteogenic calcification in vitro; INHBA expression increases during osteogenic induction alongside RUNX2 and ALP. In vivo, INHBA expression differs across fetal, healthy, and calcified valve conditions, implicating INHBA in osteogenic remodeling of VICs in calcific aortic valve disease.","method":"siRNA knockdown of INHBA in VICs, osteogenic induction in vitro, ALP and RUNX2 expression measurement, single-cell RNA-seq of human valve tissue, GWAS/bulk RNA-seq integration","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro loss-of-function with osteogenic readout plus multi-omics in vivo data; single lab","pmids":["42059080"],"is_preprint":false}],"current_model":"INHBA encodes the inhibin β-A subunit that homodimerizes to form activin A (or heterodimerizes with β-B to form activin AB, or with inhibin α to form inhibin A); it acts as a ligand of the TGF-β superfamily signaling primarily through SMAD2/3, and is regulated at the transcriptional level by factors including SPI1, C/EBPβ, BHLHE40, GLI1, and KAT8, and post-transcriptionally by miRNAs (miR-146a, miR-130b, miR-204-5p) and RNA-binding proteins (IGF2BP1/HuR); secreted INHBA/activin A drives CAF activation, macrophage M2 polarization, Treg differentiation (via SMAD2→PD-L1), epithelial-mesenchymal transition, angiogenesis suppression (via IL-8/CXCL9/CXCL10 modulation), and neuroprotection (via synaptic NMDAR→nuclear calcium→Inhba→reduced extrasynaptic NMDAR signaling), while also binding intracellular partners such as CTPS1 to enhance pyrimidine metabolism and gemcitabine resistance."},"narrative":{"mechanistic_narrative":"INHBA encodes the inhibin β-A subunit that dimerizes to form the secreted TGF-β superfamily ligand activin A, a paracrine signaling factor whose activities span tumor microenvironment remodeling, immune modulation, neuroprotection, and reproductive endocrinology [PMID:26279570, PMID:38360876, PMID:39223366, PMID:34537472]. Across diverse cancers, secreted INHBA/activin A engages SMAD2/3 signaling to activate cancer-associated fibroblasts and drive collagen/ECM deposition, proliferation, migration, and invasion [PMID:28814667, PMID:31827640, PMID:39615112]; INHBA-positive CAFs induce PD-L1 in a SMAD2-dependent autocrine loop and promote regulatory T cell differentiation, while tumor-intrinsic INHBA suppresses IFN-γ signaling to reduce CXCL9/CXCL10-driven effector T cell infiltration—effects reversed by activin A neutralizing antibodies [PMID:38360876, PMID:39223366]. INHBA further promotes macrophage M2 polarization, in part through SMAD2/TGF-β-driven CCL2 induction, integrating it into a broader immunosuppressive program [PMID:27541693, PMID:40132395, PMID:41540191]. Beyond classical SMAD signaling, INHBA acts through physical partners: it interacts with integrin ITGA6 to activate MAPK signaling, with CTPS1 to block SMURF1-mediated ubiquitination and stabilize pyrimidine metabolism for gemcitabine resistance, and serves as a required downstream mediator of COL10A1- and THBS2-driven PI3K/AKT signaling [PMID:41239468, PMID:41799510, PMID:39656597, PMID:41810913]. INHBA expression is tightly controlled transcriptionally by SPI1, C/EBPβ, GLI1, BHLHE40 and KAT8-dependent epigenetics, and post-transcriptionally by miRNAs (miR-146a, miR-130b-3p, miR-204-5p) and the m6A reader IGF2BP1/HuR axis [PMID:27541693, PMID:35338119, PMID:37644505, PMID:37097749, PMID:41445196, PMID:38676428, PMID:35689549, PMID:40132395, PMID:41540191]. In the nervous system, a BDNF→synaptic NMDAR→nuclear calcium axis upregulates Inhba, and the resulting activin A dampens extrasynaptic NMDAR-mediated calcium influx to confer neuroprotection against excitotoxicity and ischemic damage [#1 corrected to #1, #1]. In the brain, this neuroprotective role is established by [PMID:26279570] (developmental compensation) and the BDNF-driven axis [PMID:26279570].","teleology":[{"year":2000,"claim":"Established that the inhibin β-A subunit has distinct, non-redundant in vivo functions whose appropriate spatiotemporal expression—not just protein identity—determines developmental outcomes, by testing whether the β-B subunit could functionally substitute.","evidence":"Targeted knock-in replacing the Inhba mature coding region with Inhbb in mice, with phenotypic rescue analysis","pmids":["10932194"],"confidence":"High","gaps":["Does not define the molecular receptor/effector differences between β-A and β-B","Does not address adult/cancer functions"]},{"year":2009,"claim":"First linked INHBA/activin A to oncogenic proliferation and showed its expression is epigenetically controlled, framing INHBA as a tumor-promoting secreted factor.","evidence":"siRNA knockdown, recombinant activin A, follistatin inhibition, and DNA-methylation/HDAC inhibitor treatment in esophageal adenocarcinoma cell lines","pmids":["19240652"],"confidence":"Medium","gaps":["No in vivo validation","Downstream signaling pathway not defined","Specific promoter regulatory elements not mapped"]},{"year":2015,"claim":"Defined a neuroprotective signaling axis, showing activity-dependent Inhba induction restrains pathological extrasynaptic NMDAR signaling.","evidence":"Calcium imaging, synaptic/extrasynaptic NMDAR pharmacology, inhba siRNA, recombinant activin A, and an in vivo mouse stroke model","pmids":["26279570"],"confidence":"High","gaps":["Receptor/effector mechanism by which activin A reduces extrasynaptic NMDAR flux not resolved","Human relevance not established"]},{"year":2016,"claim":"Placed INHBA as a functional downstream node of miR-146a controlling macrophage polarization, connecting INHBA to immune-cell programming.","evidence":"3'-UTR luciferase reporter, miRNA gain/loss-of-function, and INHBA rescue with macrophage polarization markers and cytokine readouts","pmids":["27541693"],"confidence":"High","gaps":["Does not define how INHBA signals into macrophages","In vivo confirmation absent"]},{"year":2017,"claim":"Identified INHBA as a paracrine driver of CAF activation downstream of adrenergic stress signaling, defining its role in tumor stroma remodeling.","evidence":"Restraint-stress in vivo cancer models, β-blocker pharmacology, INHBA shRNA/siRNA, and CAF/collagen marker imaging","pmids":["28814667"],"confidence":"High","gaps":["Receptor on fibroblasts not identified here","Downstream SMAD requirement defined in later work"]},{"year":2019,"claim":"Demonstrated INHBA-driven stromal activation and tumor growth require SMAD2 and that INHBA sustains active TGF-β signaling in cancer cells.","evidence":"INHBA shRNA in ovarian and gastric cancer cells, Smad2 inhibition, xenografts, and TGF-β pathway Western blots","pmids":["31827640","30963572"],"confidence":"Medium","gaps":["Single-lab studies","Receptor complex engaged not directly identified"]},{"year":2021,"claim":"Expanded INHBA's immunomodulatory mechanism, showing INHBA+ CAFs induce PD-L1 via autocrine SMAD2 and drive Treg differentiation, with activin A neutralization as a therapeutic strategy.","evidence":"INHBA knockdown in ovarian CAFs, CAF/T cell co-culture, recombinant activin A, and anti-activin A neutralizing antibody in vivo with patient tissue analysis","pmids":["38360876"],"confidence":"High","gaps":["Direct contact molecule mediating Treg differentiation not identified","Generality across tumor types not tested here"]},{"year":2021,"claim":"Connected INHBA to therapy resistance and metabolic reprogramming, showing stromal- and tumor-intrinsic INHBA supports glycolysis and lapatinib resistance in HER2+ breast cancer.","evidence":"siRNA knockdown, metabolic profiling, lapatinib sensitivity assays, and PEAK1-dependent conditioned-medium secretome analysis in MSCs/CAFs","pmids":["35248133","34239043"],"confidence":"Medium","gaps":["Direct molecular link between INHBA and metabolic switch not defined","Single-lab studies"]},{"year":2021,"claim":"Established INHBA as a regulator of ovarian granulosa cell steroidogenesis and follicular hormone output.","evidence":"INHBA overexpression/knockdown in sheep granulosa cells with hormone ELISA and TGF-β gene expression analysis","pmids":["34537472"],"confidence":"Medium","gaps":["Mechanism of steroidogenic gene control not defined","Single species, in vitro"]},{"year":2022,"claim":"Defined multiple post-transcriptional and transcriptional control layers (circTHBS1/miR-204-5p/HuR, BHLHE40) and pharmacological suppression (metformin) governing INHBA-driven TGF-β/PI3K-Akt and Hippo signaling.","evidence":"RNA pulldown, RIP, luciferase reporters, metformin treatment, cell-cycle/senescence assays, and Verteporfin Hippo inhibition across colon and gastric cancer models","pmids":["35338119","35236827","38588888","35689549"],"confidence":"Medium","gaps":["BHLHE40 regulation lacks direct ChIP","Causal hierarchy among co-regulated pathways not resolved"]},{"year":2023,"claim":"Established m6A-dependent stabilization of INHBA mRNA by IGF2BP1 and microRNA control of an INHBA-angiogenesis axis, linking RNA regulation to downstream Smad2/3 and IL-8 signaling.","evidence":"RIP-seq, RNA pulldown, m6A PCR, RNA stability assays, BTYNB inhibitor (IGF2BP1), and miR-130b-3p mimics/inhibitors with INHBA siRNA epistasis in endothelial cells and in vivo ischemia models","pmids":["37644505","37097749"],"confidence":"High","gaps":["Receptor-level events downstream of activin A in endothelium not fully mapped","Cross-talk between BMP and TGF-β arms not dissected"]},{"year":2024,"claim":"Revealed INHBA's direct physical partners and non-SMAD effector routes—ITGA6/MAPK, CTPS1 stabilization for pyrimidine metabolism, and IFN-γ pathway suppression—broadening its mechanism beyond canonical ligand signaling.","evidence":"Co-IP/Co-IF (ITGA6), IP-MS and ubiquitination assays (CTPS1), and gain/loss-of-function with anti-activin A antibody (garetosmab) plus anti-PD-L1 across multiple mouse tumor models","pmids":["41799510","41239468","39223366"],"confidence":"Medium","gaps":["Whether intracellular CTPS1 binding reflects non-secreted INHBA pool not resolved","Structural basis of partner interactions unknown"]},{"year":2024,"claim":"Mapped transcriptional regulators (GLI1 feedback loop, KAT8 epigenetic axis, SPI1) and paracrine FAP+ stromal sources controlling INHBA in cancer and vascular senescence.","evidence":"ChIP and reporter assays (GLI1, SPI1), CRISPR multi-omics (KAT8), and FAP+ cell isolation with ELISA/SMAD2/3 readouts","pmids":["38676428","41445196","40132395","39615112"],"confidence":"Medium","gaps":["Relative contribution of each regulator in physiological tissue unknown","Single-lab studies"]},{"year":2025,"claim":"Reinforced INHBA's neuroprotective and reproductive roles, identifying its suppression in neurodegeneration and its function in thecal cell proliferation in PCOS.","evidence":"esNMDAR activation with RNA-seq and Huntington's disease mouse model rescue (memantine/FP802); spatial transcriptomics with Inhba/Smad2/E2f4 knockdown in a PCOS mouse model","pmids":["41339520","40831751"],"confidence":"Medium","gaps":["Mechanism connecting esNMDAR to Inhba transcriptional repression not detailed","Human relevance of PCOS axis not established"]},{"year":2026,"claim":"Identified additional INHBA-dependent oncogenic signaling partners (COL10A1, THBS2 via FAK/PI3K/AKT) and a role in valvular osteogenic calcification, extending its mechanistic reach.","evidence":"Co-IP and INHBA-knockdown rescue with PI3K/AKT/FAK readouts in prostate cancer; INHBA siRNA with osteogenic induction and single-cell RNA-seq in valvular interstitial cells","pmids":["39656597","41810913","42059080"],"confidence":"Medium","gaps":["THBS2-INHBA interaction inferred without direct Co-IP","Mechanism of INHBA in calcification not molecularly defined"]},{"year":null,"claim":"The receptor complexes and structural determinants linking secreted activin A versus intracellular INHBA interactions (CTPS1, integrins, collagens) to the divergent SMAD, MAPK, and PI3K/AKT outputs remain undefined, as does how a single ligand selects among context-specific effector programs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of INHBA-partner complexes","Receptor selection mechanism across tissues unknown","Distinction between secreted ligand and intracellular binding pools unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,7,15]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,19,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,23]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,7,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,7,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,13,18]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CTPS1","ITGA6","COL10A1","THBS2","IGF2BP1","SMURF1"],"other_free_text":[]}},"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 of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10932194","citation_count":162,"is_preprint":false},{"pmid":"21047417","id":"PMC_21047417","title":"Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1.","date":"2010","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/21047417","citation_count":130,"is_preprint":false},{"pmid":"24085226","id":"PMC_24085226","title":"Significance of INHBA expression in human colorectal cancer.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24085226","citation_count":76,"is_preprint":false},{"pmid":"30963572","id":"PMC_30963572","title":"INHBA gene silencing inhibits gastric cancer cell migration and invasion by impeding activation of the TGF-β signaling pathway.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30963572","citation_count":75,"is_preprint":false},{"pmid":"26279570","id":"PMC_26279570","title":"BDNF Reduces Toxic Extrasynaptic NMDA Receptor Signaling via Synaptic NMDA Receptors and Nuclear-Calcium-Induced Transcription of inhba/Activin A.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26279570","citation_count":75,"is_preprint":false},{"pmid":"28423525","id":"PMC_28423525","title":"The combination of circulating long noncoding RNAs AK001058, INHBA-AS1, MIR4435-2HG, and CEBPA-AS1 fragments in plasma serve as diagnostic markers for gastric cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28423525","citation_count":72,"is_preprint":false},{"pmid":"35236827","id":"PMC_35236827","title":"Metformin suppresses the growth of colorectal cancer by targeting INHBA to inhibit TGF-β/PI3K/AKT signaling transduction.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35236827","citation_count":68,"is_preprint":false},{"pmid":"35338119","id":"PMC_35338119","title":"CircTHBS1 drives gastric cancer progression by increasing INHBA mRNA expression and stability in a ceRNA- and RBP-dependent manner.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35338119","citation_count":66,"is_preprint":false},{"pmid":"27541693","id":"PMC_27541693","title":"MiR-146a modulates macrophage polarization in systemic juvenile idiopathic arthritis by targeting INHBA.","date":"2016","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27541693","citation_count":61,"is_preprint":false},{"pmid":"19240652","id":"PMC_19240652","title":"INHBA overexpression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcinoma.","date":"2009","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19240652","citation_count":57,"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":52,"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":37,"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":35,"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":30,"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":28,"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":"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":28,"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":26,"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":18,"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 reports","url":"https://pubmed.ncbi.nlm.nih.gov/31586103","citation_count":15,"is_preprint":false},{"pmid":"39892700","id":"PMC_39892700","title":"The YTHDF3-DT/miR-301a-3p /INHBA axis attenuates autophagy-dependent ferroptosis in lung adenocarcinoma.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39892700","citation_count":14,"is_preprint":false},{"pmid":"37528145","id":"PMC_37528145","title":"Identification of INHBA as a potential biomarker for gastric cancer through a comprehensive analysis.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37528145","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":"37097749","id":"PMC_37097749","title":"Impaired angiogenesis in diabetic critical limb ischemia is mediated by a miR-130b/INHBA signaling axis.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/37097749","citation_count":14,"is_preprint":false},{"pmid":"32509056","id":"PMC_32509056","title":"INHBA knockdown inhibits proliferation and invasion of nasopharyngeal carcinoma SUNE1 cells in vitro.","date":"2020","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32509056","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 therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33223523","citation_count":13,"is_preprint":false},{"pmid":"37539967","id":"PMC_37539967","title":"Integrated analysis of single cell and bulk RNA sequencing identifies CTHRC1+ INHBA+ CAF as drivers of colorectal cancer progression.","date":"2023","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/37539967","citation_count":12,"is_preprint":false},{"pmid":"38588888","id":"PMC_38588888","title":"INHBA regulates Hippo signaling to confer 5-FU chemoresistance mediated by cellular senescence in colon cancer cells.","date":"2024","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38588888","citation_count":10,"is_preprint":false},{"pmid":"40355814","id":"PMC_40355814","title":"INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinoma.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40355814","citation_count":9,"is_preprint":false},{"pmid":"37940978","id":"PMC_37940978","title":"INHBA gene silencing inhibits proliferation, migration, and invasion of osteosarcoma cells by repressing TGF-β signaling pathway activation.","date":"2023","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/37940978","citation_count":9,"is_preprint":false},{"pmid":"39615112","id":"PMC_39615112","title":"FAP+ gastric cancer mesenchymal stromal cells via paracrining INHBA and remodeling ECM promote tumor progression.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39615112","citation_count":9,"is_preprint":false},{"pmid":"36525859","id":"PMC_36525859","title":"Exploration the role of INHBA in Hu sheep granulosa cells using RNA-Seq.","date":"2022","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/36525859","citation_count":9,"is_preprint":false},{"pmid":"36190571","id":"PMC_36190571","title":"BMSCs overexpressed ISL1 reduces the apoptosis of islet cells through ANLN carrying exosome, INHBA, and caffeine.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/36190571","citation_count":9,"is_preprint":false},{"pmid":"33090398","id":"PMC_33090398","title":"LncRNA INHBA-AS1 promotes colorectal cancer cell proliferation by sponging miR-422a to increase AKT1 axis.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33090398","citation_count":9,"is_preprint":false},{"pmid":"35093789","id":"PMC_35093789","title":"Extracellular vesicles extracted from bone marrow mesenchymal stem cells carrying MicroRNA-342-3p inhibit the INHBA/IL13Rα2 axis to suppress the growth and metastasis of breast cancer.","date":"2022","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35093789","citation_count":9,"is_preprint":false},{"pmid":"21576276","id":"PMC_21576276","title":"Coding regions of INHBA, SFRP4 and HOXA10 are not implicated in familial endometriosis linked to chromosome 7p13-15.","date":"2011","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/21576276","citation_count":9,"is_preprint":false},{"pmid":"32970737","id":"PMC_32970737","title":"A polymorphism in the cachexia-associated gene INHBA predicts efficacy of regorafenib in patients with refractory metastatic colorectal cancer.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32970737","citation_count":9,"is_preprint":false},{"pmid":"38329386","id":"PMC_38329386","title":"INHBA is Enriched in HPV-negative Oropharyngeal Squamous Cell Carcinoma and Promotes Cancer Progression.","date":"2024","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/38329386","citation_count":8,"is_preprint":false},{"pmid":"38676428","id":"PMC_38676428","title":"Positive GLI1/INHBA feedback loop drives tumor progression in gastric cancer.","date":"2024","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/38676428","citation_count":8,"is_preprint":false},{"pmid":"35216189","id":"PMC_35216189","title":"DNA Hypomethylation Is Associated with the Overexpression of INHBA in Upper Tract Urothelial Carcinoma.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35216189","citation_count":8,"is_preprint":false},{"pmid":"32141551","id":"PMC_32141551","title":"LncRNA INHBA-AS1 promotes cell growth, migration, and invasion of oral squamous cell carcinoma by sponging miR-143-3p.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32141551","citation_count":8,"is_preprint":false},{"pmid":"38419562","id":"PMC_38419562","title":"Elevated INHBA Promotes Tumor Progression of Cervical Cancer.","date":"2024","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/38419562","citation_count":7,"is_preprint":false},{"pmid":"33977869","id":"PMC_33977869","title":"Silencing of long noncoding INHBA antisense RNA1 suppresses proliferation, migration, and extracellular matrix deposition in human hypertrophic scar fibroblasts via regulating microRNA-141-3p/myeloid cell leukemia 1 axis.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/33977869","citation_count":7,"is_preprint":false},{"pmid":"34103052","id":"PMC_34103052","title":"An immune-related model based on INHBA, JAG2 and CCL19 to predict the prognoses of colon cancer patients.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/34103052","citation_count":7,"is_preprint":false},{"pmid":"38062804","id":"PMC_38062804","title":"The New Role of HNF1A-NAS1/miR-214/INHBA Signaling Axis in Colorectal Cancer.","date":"2023","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/38062804","citation_count":6,"is_preprint":false},{"pmid":"39857255","id":"PMC_39857255","title":"miR-134-3p Regulates Cell Proliferation and Apoptosis by Targeting INHBA via Inhibiting the TGF-β/PI3K/AKT Pathway in Sheep Granulosa Cells.","date":"2024","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/39857255","citation_count":6,"is_preprint":false},{"pmid":"37086585","id":"PMC_37086585","title":"MiR-29c-5p regulates the function of buffalo granulosa cells to induce follicular atresia by targeting INHBA.","date":"2023","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/37086585","citation_count":5,"is_preprint":false},{"pmid":"33970982","id":"PMC_33970982","title":"Effect of Mouse Ovarian Vitrification on Promoter Methylation of Inhba and Inhbb in Granulosa Cells of Follicles.","date":"2021","source":"Cryo letters","url":"https://pubmed.ncbi.nlm.nih.gov/33970982","citation_count":5,"is_preprint":false},{"pmid":"23767829","id":"PMC_23767829","title":"Changes in the reproductive endocrine function in rat following intraovary microinjection of inhba overexpression lentivirus vectors.","date":"2013","source":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23767829","citation_count":5,"is_preprint":false},{"pmid":"40132395","id":"PMC_40132395","title":"INHBA, transcriptionally activated by SPI1, facilitates gastric cancer progression by inducing macrophage recruitment and M2 polarization via activating the TGF-β signaling to increase CCL2.","date":"2025","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/40132395","citation_count":4,"is_preprint":false},{"pmid":"10912684","id":"PMC_10912684","title":"Linkage mapping of the ovine alpha-inhibin (INHA) beta(A)-inhibin/activin (INHBA) and beta(B)-inhibin/activin (INHBB) genes.","date":"2000","source":"The Journal of heredity","url":"https://pubmed.ncbi.nlm.nih.gov/10912684","citation_count":4,"is_preprint":false},{"pmid":"35042829","id":"PMC_35042829","title":"Dysregulation of Npas4 and Inhba expression and an altered excitation-inhibition balance are associated with cognitive deficits in DBA/2 mice.","date":"2022","source":"Learning & memory (Cold Spring Harbor, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35042829","citation_count":3,"is_preprint":false},{"pmid":"41013408","id":"PMC_41013408","title":"INHBA knockdown inhibits renal fibrosis in mice following ischemia-reperfusion injury by suppressing activation of the TGF-β/Smad signaling pathway.","date":"2025","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/41013408","citation_count":3,"is_preprint":false},{"pmid":"41540191","id":"PMC_41540191","title":"INHBA, regulated by C/EBPβ, induces M2 macrophage polarization to promote tumor metastasis and growth via activating the PI3K/AKT pathway in gastric cancer.","date":"2026","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41540191","citation_count":2,"is_preprint":false},{"pmid":"39656597","id":"PMC_39656597","title":"COL10A1 Facilitates Prostate Cancer Progression by Interacting With INHBA to Activate the PI3K/AKT Pathway.","date":"2024","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39656597","citation_count":2,"is_preprint":false},{"pmid":"41445196","id":"PMC_41445196","title":"Targeting KAT8 alleviates vascular senescence by modulating the INHBA/TGF-β pathway.","date":"2025","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41445196","citation_count":1,"is_preprint":false},{"pmid":"41339520","id":"PMC_41339520","title":"Inhba, Homer1 and Bdnf are major targets of transcriptomic dysregulation by neurodegenerative disease-associated excitotoxic NMDA receptor signaling.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41339520","citation_count":0,"is_preprint":false},{"pmid":"40754873","id":"PMC_40754873","title":"INHBA: A Protein-coding Gene Closely Related to Tumour Diseases.","date":"2025","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40754873","citation_count":0,"is_preprint":false},{"pmid":"41239468","id":"PMC_41239468","title":"INHBA promotes chemoresistance in pancreatic cancer by enhancing CTPS1 stability and mediating pyrimidine metabolism.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/41239468","citation_count":0,"is_preprint":false},{"pmid":"41799510","id":"PMC_41799510","title":"INHBA Promotes the Progression of Gastric Cancer by Activating MAPK Signaling Pathway via Targeting ITGA6.","date":"2026","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/41799510","citation_count":0,"is_preprint":false},{"pmid":"40831751","id":"PMC_40831751","title":"Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/40831751","citation_count":0,"is_preprint":false},{"pmid":"37962399","id":"PMC_37962399","title":"Pharmacological investigation of vitamin E with combined oral contraceptives on INHBA gene against PCOS that intricate through melatonin PKC pathway.","date":"2023","source":"Systems biology in reproductive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37962399","citation_count":0,"is_preprint":false},{"pmid":"41218586","id":"PMC_41218586","title":"Rhapontigenin inhibits inflammation and senescence of chondrocytes from patients with osteoarthritis by targeting INHBA.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41218586","citation_count":0,"is_preprint":false},{"pmid":"42143353","id":"PMC_42143353","title":"A multi-omics dissection of INHBA+ CAF-mediated epithelial-mesenchymal transition and immune suppression in colorectal cancer.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42143353","citation_count":0,"is_preprint":false},{"pmid":"42059080","id":"PMC_42059080","title":"Multiomics Analysis Reveals Stromal Cell State Changes and INHBA-Associated Remodeling in Calcific Aortic Valve Disease.","date":"2026","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/42059080","citation_count":0,"is_preprint":false},{"pmid":"41326944","id":"PMC_41326944","title":"Machine learning identifies INHBA DPT ADH7 FBP2 and GPR155 as diagnostic biomarkers for gastric cancer.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41326944","citation_count":0,"is_preprint":false},{"pmid":"41810913","id":"PMC_41810913","title":"THBS2 Promotes Prostate Cancer Malignancy via INHBA-Dependent FAK/PI3K/AKT Signaling Activation.","date":"2026","source":"Analytical cellular pathology (Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/41810913","citation_count":0,"is_preprint":false},{"pmid":"33015761","id":"PMC_33015761","title":"LncRNA INHBA-AS1 promotes cell growth, migration, and invasion of oral squamous cell carcinoma by sponging miR-143-3p.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33015761","citation_count":0,"is_preprint":false},{"pmid":"42173078","id":"PMC_42173078","title":"G-CSF enhances neutrophil function with potential involvement of INHBA during Aspergillus fumigatus infection.","date":"2026","source":"International journal of medical microbiology : IJMM","url":"https://pubmed.ncbi.nlm.nih.gov/42173078","citation_count":0,"is_preprint":false},{"pmid":"42111260","id":"PMC_42111260","title":"Correction: Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice.","date":"2026","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/42111260","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.12.675858","title":"Transcriptomic and proteomic dynamics of ovarian follicle group culture resemble  <i>in vivo</i>  folliculogenesis","date":"2025-09-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.12.675858","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.26.645498","title":"Crucial roles of mesenchymal  <i>Gata2</i>  in murine epididymal development","date":"2025-03-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.26.645498","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.29.656801","title":"The RNA-binding protein TRIM71 is essential for hearing in humans and mice and regulates the timing of auditory sensory organ development","date":"2025-05-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.29.656801","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.04.647177","title":"Integrin-TGFβ axis induces partial EMT in basal-like cells to lead collective invasion","date":"2025-04-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.04.647177","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.06.631425","title":"Delineating JunB’s Crucial Function in Mature Th17 Cells through Inducible Targeted Protein Degradation","date":"2025-01-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.06.631425","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.11.617817","title":"Load activated FGFR and beta1 integrins target distinct chondrocyte mechano-response genes","date":"2024-10-13","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.11.617817","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.20.608775","title":"Minipuberty regulates reproductive lifespan and ovarian follicular loss in a mouse model with reduced minipubertal gonadotropin levels","date":"2024-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.20.608775","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.25.668405","title":"A fibroblast-centric network drives cold fibrosis in the tumor microenvironment of lung squamous cell carcinoma","date":"2025-08-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.25.668405","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.01.657221","title":"A Single-cell and Spatially Resolved Cell Atlas of Human Esophageal Squamous Cell Carcinoma","date":"2025-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.01.657221","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46938,"output_tokens":9789,"usd":0.143824,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20429,"output_tokens":5229,"usd":0.116435,"stage2_stop_reason":"end_turn"},"total_usd":0.260259,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Replacement of the Inhba mature-protein coding region with Inhbb (creating the InhbaBK knock-in allele) rescued the craniofacial/palate/tooth phenotypes of Inhba-null mice but produced novel somatic, testicular, genital, and hair-growth phenotypes, demonstrating that functional compensation within the TGF-β superfamily depends on appropriate spatiotemporal expression and that Inhba and Inhbb have overlapping but non-identical in vivo activities.\",\n      \"method\": \"Gene knock-in / targeted replacement (Inhba locus replaced with Inhbb coding sequence), in vivo mouse genetics, phenotypic rescue analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vivo reconstitution with allelic replacement, rigorous genetic rescue experiment, replicated across multiple phenotypic endpoints\",\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/activin A homodimer). The resulting activin A then reduces extrasynaptic NMDA-receptor-mediated calcium influx, thereby protecting neurons against mitochondrial dysfunction and excitotoxicity. This BDNF → synaptic NMDAR → nuclear calcium → Inhba → reduced extrasynaptic NMDAR signaling axis confers neuroprotection against ischemic brain damage in a mouse stroke model.\",\n      \"method\": \"Primary neuron live-cell calcium imaging, pharmacological block of synaptic vs. extrasynaptic NMDARs, siRNA knockdown of inhba, recombinant activin A application, in vivo mouse stroke model, nuclear calcium reporters\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, pharmacology, KD, recombinant protein, in vivo model), causal pathway established with specific readouts\",\n      \"pmids\": [\"26279570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"INHBA overexpression in esophageal adenocarcinoma (EAC) cell lines promotes cell proliferation; exogenous activin A increases proliferation of FLO and OE-33 cells, while follistatin (activin inhibitor) and INHBA-targeting siRNA reduce proliferation. INHBA expression in EAC cell lines is upregulated by treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine and the HDAC inhibitor trichostatin A, indicating that promoter demethylation and histone acetylation regulate INHBA expression.\",\n      \"method\": \"siRNA knockdown, exogenous recombinant activin A treatment, follistatin inhibitor treatment, 5-AZA and trichostatin A epigenetic drug treatment, cell proliferation assays, real-time RT-PCR, IHC\",\n      \"journal\": \"Journal of thoracic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (gain/loss-of-function, inhibitor, epigenetic drug) in single lab, two orthogonal mechanistic approaches\",\n      \"pmids\": [\"19240652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cancer-cell-derived INHBA (inhibin β-A/activin A) induces cancer-associated fibroblast (CAF) activation in ovarian cancer models. Adrenergic (stress) signaling increases INHBA production by cancer cells; ablating INHBA expression decreases CAF phenotype and associated collagen/ECM deposition both in vitro and in vivo. This identifies INHBA as a paracrine driver of the CAF phenotype downstream of adrenergic signaling.\",\n      \"method\": \"In vivo restraint-stress mouse models of ovarian/breast/colon cancer, β-blocker pharmacology, bioinformatics-guided systems biology, siRNA/shRNA ablation of INHBA in vitro and in vivo, immunofluorescence/IHC for CAF markers and collagens\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cancer models, in vivo and in vitro validation, pharmacological and genetic perturbation of INHBA, consistent results across systems\",\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 mediates macrophage M1/M2 polarization: INHBA overexpression rescues M1 cytokine production (IL-6, IL-12, TNF-α) suppressed by miR-146a, and rescues M2 markers (Arg1, CCL17, CCL22) suppressed by miR-146a inhibition. Thus miR-146a regulates monocyte polarization through INHBA.\",\n      \"method\": \"3'-UTR luciferase reporter assay, miRNA overexpression/knockdown, INHBA overexpression/knockdown rescue experiments, cytokine measurement, flow cytometry for macrophage polarization markers\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct 3'-UTR binding validated by luciferase assay, epistatic rescue experiments establish INHBA as functional downstream target, multiple orthogonal methods\",\n      \"pmids\": [\"27541693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"INHBA knockdown in ovarian cancer cells impairs xenograft tumor growth in vivo by reducing stromal fibroblast activation. Mechanistically, INHBA-induced stromal fibroblast activation depends on Smad2 signaling; inhibiting Smad2 pathway reverses INHBA-driven fibroblast activation.\",\n      \"method\": \"shRNA knockdown of INHBA in OC cells, xenograft mouse model, Smad2 pathway inhibition, in vitro co-culture fibroblast activation assays\",\n      \"journal\": \"Disease markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft plus Smad2 inhibitor rescue; single lab but two orthogonal approaches (genetic KD + pharmacological inhibition)\",\n      \"pmids\": [\"31827640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"INHBA gene silencing via shRNA inhibits TGF-β signaling pathway activation in gastric cancer cells, reducing cell migration, invasion, proliferation, and tumor growth in a xenograft nude mouse model. Conversely, INHBA is required to maintain active TGF-β signaling in GC cells.\",\n      \"method\": \"shRNA knockdown of INHBA, Western blot for TGF-β pathway proteins, migration/invasion/proliferation assays, xenograft tumor model in nude mice\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vitro and in vivo with defined pathway readout; single lab\",\n      \"pmids\": [\"30963572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INHBA in ovarian CAFs induces PD-L1 expression in an autocrine manner through SMAD2-dependent signaling, and INHBA+ CAFs promote regulatory T cell (Treg) differentiation via direct cell contact. Neutralizing Activin A (INHBA homodimer) antibody in vivo attenuates tumor progression and reduces pro-tumorigenic myofibroblasts and macrophages.\",\n      \"method\": \"INHBA knockdown in human ovarian CAFs, T cell/CAF co-culture assay for Treg differentiation, recombinant Activin A treatment, anti-Activin A neutralizing antibody in vivo in mouse ovarian cancer models, SMAD2 pathway analysis, spatiotemporal patient tissue analysis\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KD, recombinant protein, neutralizing antibody in vivo), mechanistic pathway (INHBA→SMAD2→PD-L1) and cellular consequence (Treg differentiation) both established, patient tissue validation\",\n      \"pmids\": [\"38360876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INHBA promotes colon cancer cell proliferation, migration, and invasion through upregulation of versican (VCAN). The INHBA-VCAN correlation was verified by immunoprecipitation, and INHBA interference inhibited aggressive behavior by downregulating VCAN.\",\n      \"method\": \"Immunoprecipitation, siRNA knockdown of INHBA and VCAN, overexpression, CCK-8/colony formation, wound healing, Transwell assays\",\n      \"journal\": \"The Journal of international medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP to establish INHBA-VCAN relationship, single lab, limited mechanistic follow-up on how INHBA regulates VCAN\",\n      \"pmids\": [\"34130530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In HER2+ basal breast cancer cells, INHBA knockdown slows growth, increases lapatinib sensitivity, and shifts cellular metabolism from glycolysis to oxidative phosphorylation, indicating INHBA supports a glycolytic and invasive phenotype in the basal subtype.\",\n      \"method\": \"siRNA knockdown screen, 2D and 3D cell culture validation, metabolic profiling, lapatinib sensitivity assays\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal readouts (growth, drug sensitivity, metabolomics) in multiple cell lines; single lab\",\n      \"pmids\": [\"35248133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MSC-derived INHBA/activin-A is a necessary paracrine factor mediating lapatinib resistance of HER2+ breast cancer cells in a PEAK1-dependent stromal axis (SNAI2-PEAK1-INHBA). INHBA in conditioned media from PEAK1-expressing MSCs promotes lapatinib resistance, as established by analysis of PEAK1-dependent secreted factors.\",\n      \"method\": \"Conditioned medium transfer experiments, PEAK1 knockdown/overexpression in MSCs and CAFs, secretome analysis, single-cell cyclic immunofluorescence (CycIF), co-culture systems\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — INHBA identified as necessary secreted factor by conditioned media analysis and genetic perturbation; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"34239043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Metformin suppresses CRC cell proliferation causing G1/S arrest by downregulating INHBA expression, which blocks TGF-β signaling activation and downstream PI3K/Akt pathway activity, leading to reduced cyclin D1.\",\n      \"method\": \"INHBA knockdown and overexpression in CRC cells, metformin treatment, cell cycle analysis (flow cytometry), Western blot for TGF-β/PI3K/Akt pathway components, proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function with defined pathway readout; single lab, two orthogonal perturbations (genetic + pharmacological)\",\n      \"pmids\": [\"35236827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircTHBS1 promotes INHBA expression via two mechanisms: (1) sponging miR-204-5p to relieve repression of INHBA mRNA, and (2) enhancing HuR-mediated mRNA stability of INHBA. Elevated INHBA consequently activates the TGF-β pathway to drive gastric cancer malignancy.\",\n      \"method\": \"RNA pulldown, luciferase reporter assay, RNA immunoprecipitation (RIP), gain/loss-of-function assays in vitro and in vivo, transcriptome analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two distinct RNA-level mechanisms validated by RIP and luciferase assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35338119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNA-binding protein IGF2BP1 binds and stabilizes INHBA mRNA (via m6A-dependent mechanism), leading to higher INHBA protein expression and activation of Smad2/3 signaling, which promotes invasion and migration of esophageal squamous cancer cells. IGF2BP1 also interacts with G3BP1, and G3BP1 knockdown similarly downregulates INHBA-Smad2/3 signaling.\",\n      \"method\": \"RNA immunoprecipitation sequencing (RIP-seq), RNA pulldown, gene-specific m6A PCR, RNA stability assays, immunofluorescence, mass spectrometry, siRNA knockdown, in vivo metastasis assays, small-molecule inhibitor BTYNB\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct RNA-binding established by RIP-seq and pulldown, m6A-dependent stabilization mechanism confirmed, downstream Smad2/3 signaling validated, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37644505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-130b-3p directly targets and represses INHBA mRNA. INHBA repression (either by miR-130b overexpression or INHBA siRNA) induces IL-8 expression, a pro-angiogenic chemokine, and improves revascularization in diabetic ischemic limbs in vivo. Thus a miR-130b/INHBA axis controls angiogenesis by modulating BMP/TGF-β signaling in endothelial cells.\",\n      \"method\": \"miRNA target prediction with experimental validation, miRNA mimic/inhibitor transfection in endothelial cells, siRNA knockdown of INHBA, in vitro angiogenic assays (proliferation, migration, sprouting), in vivo femoral artery ligation in diabetic (db/db) mice, RNA-seq/GSEA\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct targeting validated, INHBA siRNA recapitulates miR-130b phenotype (epistasis), in vivo validation in disease model, multiple orthogonal methods\",\n      \"pmids\": [\"37097749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tumor-intrinsic INHBA suppresses the IFN-γ signaling pathway, leading to (1) reduced IFN-γ-induced PD-L1 expression (causing poor response to anti-PD-L1 therapy) and (2) decreased secretion of IFN-γ-stimulated chemokines CXCL9 and CXCL10, impairing effector T cell infiltration into tumors. Activin A-specific antibody garetosmab improves anti-tumor immunity and synergizes with anti-PD-L1 antibody atezolizumab.\",\n      \"method\": \"INHBA gain/loss-of-function in CT26, MC38, B16, and 4T1 mouse tumor models, anti-PD-L1 antibody treatment, anti-Activin A antibody (garetosmab) treatment, flow cytometry for T cell infiltration, IFN-γ signaling pathway analysis, cytokine/chemokine measurement\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo tumor models, genetic gain/loss-of-function, pharmacological neutralization, mechanistic pathway (INHBA→IFN-γ suppression→CXCL9/10 reduction→T cell exclusion) established with multiple readouts\",\n      \"pmids\": [\"39223366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT8 (lysine acetyltransferase 8) suppresses vascular senescence by epigenetically regulating the INHBA/TGF-β/P15 signaling axis. KAT8 deficiency increases INHBA expression, promoting TGF-β-mediated senescence, while KAT8 overexpression attenuates vascular senescence. hsa-miR-339-3p is identified as responsible for age-related KAT8 downregulation upstream of this axis.\",\n      \"method\": \"CRISPR-Cas9 loss-of-function and gain-of-function in endothelial cells and mice (C57BL/6J and ApoE-/-), integrated miRNA-seq/ATAC-seq/RNA-seq multi-omics analysis, senescence assays\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics plus genetic perturbation in vitro and in vivo; INHBA identified as downstream target of KAT8 within this axis; single lab\",\n      \"pmids\": [\"41445196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GLI1 (Hedgehog transcription factor) transcriptionally upregulates INHBA in gastric cancer. Elevated INHBA in turn activates Smads signaling, which transcriptionally activates GLI1, forming a positive GLI1/INHBA feedback loop that drives GC tumorigenesis. Additionally, H. pylori upregulates GLI1 via m6A modification through the FTO/YTHDF2/GLI1 pathway, feeding into this loop.\",\n      \"method\": \"Chromatin immunoprecipitation, reporter assays, gain/loss-of-function for GLI1 and INHBA, in vivo mouse tumor models disrupting GLI1-INHBA interaction, m6A modification analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays establish transcriptional regulation; epistatic feedback loop demonstrated in vivo; single lab\",\n      \"pmids\": [\"38676428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"INHBA promotes chemoresistance in pancreatic cancer by physically interacting with CTPS1 (cytidine triphosphate synthase 1) and competitively inhibiting SMURF1-mediated ubiquitination of CTPS1, thereby stabilizing CTPS1 protein and enhancing pyrimidine metabolism that supports gemcitabine resistance.\",\n      \"method\": \"Immunoprecipitation mass spectrometry (to identify CTPS1 as binding partner), co-immunoprecipitation, ubiquitination assays, drug sensitivity analysis, xenograft mouse model, EdU/flow cytometry/colony formation assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding partner identified by IP-MS and validated by co-IP; ubiquitination mechanism established; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"41239468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAP+ gastric cancer mesenchymal stromal cells secrete INHBA via paracrine signaling to activate SMAD2/3 signaling in gastric cancer cells, increasing their proliferation and migration. These cells also induce collagen deposition that acts via integrin ITGB1 to phosphorylate FAK and YAP, promoting invasion and stemness.\",\n      \"method\": \"FAP+ cell isolation by flow cytometry, conditioned medium/ELISA experiments, Western blot for SMAD2/3, Masson's trichrome staining, IHC, transcriptomic sequencing\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — paracrine INHBA secretion measured by ELISA, downstream SMAD2/3 activation by Western blot, mechanistic pathway established; single lab\",\n      \"pmids\": [\"39615112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"INHBA promotes gastric cancer progression by interacting with ITGA6 (integrin alpha-6) to activate the MAPK signaling pathway. Co-immunoprecipitation and co-immunofluorescence confirmed the INHBA-ITGA6 interaction; rescue experiments demonstrated that ITGA6 mediates INHBA-driven MAPK activation, proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), co-immunofluorescence, RNA-seq pathway analysis, Western blot, rescue experiments with ITGA6 manipulation, in vivo xenograft models, RT-qPCR, IHC\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct INHBA-ITGA6 interaction validated by reciprocal Co-IP and Co-IF; rescue experiments support epistatic relationship; single lab\",\n      \"pmids\": [\"41799510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"INHBA confers 5-FU chemoresistance in colon cancer by promoting cellular senescence and inactivating the Hippo signaling pathway (as validated using the Hippo pathway inhibitor Verteporfin). INHBA knockdown enhanced 5-FU sensitivity, inhibited proliferation, promoted apoptosis, and reduced senescent cell proportion and senescence markers (IL-6, IL-8).\",\n      \"method\": \"INHBA knockdown/overexpression, 5-FU drug sensitivity assays, cellular senescence assays (SA-β-gal, senescence marker expression), Verteporfin (Hippo inhibitor) treatment, in vivo xenograft model, flow cytometry for cell cycle\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic perturbation combined with pathway-specific pharmacological inhibitor (Verteporfin) establishes Hippo pathway involvement; in vivo validation; single lab\",\n      \"pmids\": [\"38588888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Extrasynaptic NMDA receptor (esNMDAR) activation suppresses Inhba transcription in hippocampal neurons as part of a broad neurodegenerative transcriptional dysregulation program. In a Huntington's disease mouse model, treatment with memantine or FP802 (NMDAR/TRPM4 complex inhibitor) restores Inhba expression along with Bdnf and Homer1, attenuating disease progression markers. Inhba is identified as a major neuroprotective gene whose suppression contributes to neurodegeneration.\",\n      \"method\": \"Primary hippocampal neuron cultures with pharmacological esNMDAR activation, RNA-seq, Huntington's disease mouse model (memantine and FP802 treatment), quantitative gene expression analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro neuronal model and in vivo HD mouse model with pharmacological rescue; Inhba identified as key downstream target; single lab, multiple models\",\n      \"pmids\": [\"41339520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INHBA transfection in sheep granulosa cells: overexpression significantly decreases activin A and estradiol secretion while increasing inhibin A and progesterone secretion. INHBA overexpression also decreased FSH-β subunit expression. INHBA knockdown inhibited expression of multiple TGF-β-related genes. These results establish INHBA as a regulator of granulosa cell hormone synthesis and follicular development.\",\n      \"method\": \"In vitro transfection (overexpression and siRNA knockdown) in sheep granulosa cells, hormone ELISA, RT-qPCR/Western blot for cell cycle and apoptosis genes, proliferation assays\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional perturbation (OE and KD) with multiple hormonal readouts; single lab, clean functional phenotype\",\n      \"pmids\": [\"34537472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Spatial transcriptomics in a PCOS mouse model identified an Inhba/Smad2/E2f4 signaling axis as a key regulator of Lrp2-high thecal cell proliferation. Knockdown of any component of this axis (Inhba, Smad2, or E2f4) significantly suppressed thecal cell proliferation in vitro, with the greatest effect from Inhba silencing. This axis is implicated in androgen excess in PCOS.\",\n      \"method\": \"Spatial transcriptomics, siRNA knockdown of Inhba/Smad2/E2f4, EdU incorporation assay, flow cytometry for cell cycle, DHEA-induced PCOS mouse model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — spatial transcriptomics plus functional validation by siRNA knockdown with cell cycle readout; single lab\",\n      \"pmids\": [\"40831751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a preprint, integrin α2 (Itgα2) engagement with collagen I induces INHBA expression in basal-like breast cancer cells, activating TGF-β signaling which upregulates vimentin while preserving epithelial junction gene expression, thus driving a partial EMT (leader cell phenotype) that enables collective invasion. Itgα2 also promotes ECM degradation through a TGF-β-independent mechanism.\",\n      \"method\": \"Collagen I-responsive cell subset identification, Itgα2 perturbation, INHBA expression analysis, TGF-β signaling readouts, vimentin and E-cadherin/junction gene quantification, in vitro collective invasion assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, mechanistic pathway proposed with supporting cell biology data but not yet peer-reviewed; limited mechanistic depth on how Itgα2 induces INHBA\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a preprint, TRIM71 represses Inhba (and Tgfbr2) expression in cochlear progenitor cells. Loss of TRIM71 function leads to premature hair cell differentiation; analysis of Inhba;Tgfbr1 double knockout mice indicates TRIM71 maintains hair cell progenitors in a proliferative undifferentiated state by restricting TGF-β-type signaling, placing Inhba downstream of TRIM71 in this developmental pathway.\",\n      \"method\": \"Conditional Trim71 knockout mice, Inhba;Tgfbr1 double knockout mice, transcriptomic profiling of cochlear progenitors, in vivo developmental timing analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — double knockout genetic epistasis in mouse development; preprint, single lab; places Inhba in TGF-β pathway downstream of TRIM71 but requires peer review\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a preprint, mesenchyme-specific deletion of Gata2 reduces Inhba expression in the epididymal mesenchyme and impairs epithelial proliferation and epididymal coiling. This identifies Inhba as downstream of GATA2 in androgen-independent mesenchymal signaling required for epididymal development.\",\n      \"method\": \"Conditional mesenchyme-specific Gata2 knockout mice, dihydrotestosterone supplementation rescue experiments, Inhba expression analysis by RT-qPCR/IHC, epithelial proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function with defined phenotype; preprint, single lab; Inhba placed downstream of GATA2 but not directly validated with Inhba rescue\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In JunB-deficient Th17 cells, Inhba (encoding activin A) is identified as a JunB transcriptional target. Supplementation with recombinant activin A restores IL-17A and Rorc expression during pathogenic Th17 cell differentiation in JunB-deficient conditions, establishing activin A as a functional downstream effector of JunB-driven Th17 differentiation.\",\n      \"method\": \"dTAG protein degradation of JunB in Th17 cells, transcriptomic analysis, recombinant activin A rescue, flow cytometry for IL-17A and RORγt, in vitro and in vivo Th17 differentiation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional rescue with recombinant activin A supports INHBA as JunB target; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"INHBA transcription in colon cancer cells is directly activated by the transcription factor BHLHE40, as established through database analysis and experimental validation showing BHLHE40 modulates INHBA expression; BHLHE40 knockdown suppresses INHBA and reduces colon cancer cell proliferation and migration.\",\n      \"method\": \"siRNA knockdown of BHLHE40, Western blot and RT-qPCR, database analysis (JASPAR, PROMO, ENCODE), CCK-8 proliferation and wound healing assays\",\n      \"journal\": \"Journal of clinical laboratory analysis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcription factor-target relationship inferred from database prediction and knockdown; no direct promoter binding assay (e.g., ChIP) performed; single lab\",\n      \"pmids\": [\"35689549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPI1 (PU.1) transcription factor binds to the INHBA promoter and transcriptionally activates INHBA expression in gastric cancer cells. INHBA in turn activates TGF-β signaling to upregulate CCL2, which promotes macrophage recruitment and M2 polarization, facilitating GC cell proliferation, migration, and invasion.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), Western blot for TGF-β pathway, macrophage recruitment assays, co-culture experiments, in vivo xenograft model\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding validated by ChIP and luciferase reporter; downstream TGF-β/CCL2 pathway established; single lab\",\n      \"pmids\": [\"40132395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"COL10A1 directly interacts with INHBA (co-immunoprecipitation) and facilitates PI3K/AKT pathway phosphorylation in prostate cancer cells and mouse models. INHBA knockdown reverses the oncogenic effects of COL10A1 overexpression, establishing INHBA as a required downstream mediator of COL10A1-driven PI3K/AKT signaling and PCa progression.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), Western blot for PI3K/AKT phosphorylation, siRNA knockdown of INHBA (rescue experiment), CCK-8, colony formation, flow cytometry, Transwell, wound-healing assays, mouse models\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction by Co-IP with functional rescue; PI3K/AKT signaling readout; single lab\",\n      \"pmids\": [\"39656597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"THBS2 directly interacts with INHBA to activate the FAK/PI3K/AKT signaling pathway in prostate cancer. INHBA knockdown reverses the oncogenic effects of THBS2 overexpression, demonstrating epistatic dependence of THBS2-driven signaling on INHBA.\",\n      \"method\": \"STRING interaction prediction, Western blot for FAK/PI3K/AKT phosphorylation, INHBA knockdown rescue experiments, overexpression/knockdown functional assays (CCK-8, invasion, EMT markers)\",\n      \"journal\": \"Analytical cellular pathology (Amsterdam)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction inferred from STRING and Western blot pathway analysis without direct Co-IP validation; single lab\",\n      \"pmids\": [\"41810913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"C/EBPβ transcriptionally upregulates INHBA in gastric cancer cells (validated by dual-luciferase reporter and ChIP). INHBA then induces M2 macrophage polarization and activates a PI3K/AKT/TGF-β positive feedback loop, promoting tumor metastasis and growth.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP, INHBA gain/loss-of-function, macrophage polarization co-culture assays (CIBERSORT), in vitro/in vivo tumor models\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding validated by ChIP and reporter; macrophage polarization and PI3K/AKT axis established; single lab\",\n      \"pmids\": [\"41540191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"INHBA silencing in valvular interstitial cells (VICs) reduces osteogenic calcification in vitro; INHBA expression increases during osteogenic induction alongside RUNX2 and ALP. In vivo, INHBA expression differs across fetal, healthy, and calcified valve conditions, implicating INHBA in osteogenic remodeling of VICs in calcific aortic valve disease.\",\n      \"method\": \"siRNA knockdown of INHBA in VICs, osteogenic induction in vitro, ALP and RUNX2 expression measurement, single-cell RNA-seq of human valve tissue, GWAS/bulk RNA-seq integration\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro loss-of-function with osteogenic readout plus multi-omics in vivo data; single lab\",\n      \"pmids\": [\"42059080\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INHBA encodes the inhibin β-A subunit that homodimerizes to form activin A (or heterodimerizes with β-B to form activin AB, or with inhibin α to form inhibin A); it acts as a ligand of the TGF-β superfamily signaling primarily through SMAD2/3, and is regulated at the transcriptional level by factors including SPI1, C/EBPβ, BHLHE40, GLI1, and KAT8, and post-transcriptionally by miRNAs (miR-146a, miR-130b, miR-204-5p) and RNA-binding proteins (IGF2BP1/HuR); secreted INHBA/activin A drives CAF activation, macrophage M2 polarization, Treg differentiation (via SMAD2→PD-L1), epithelial-mesenchymal transition, angiogenesis suppression (via IL-8/CXCL9/CXCL10 modulation), and neuroprotection (via synaptic NMDAR→nuclear calcium→Inhba→reduced extrasynaptic NMDAR signaling), while also binding intracellular partners such as CTPS1 to enhance pyrimidine metabolism and gemcitabine resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INHBA encodes the inhibin β-A subunit that dimerizes to form the secreted TGF-β superfamily ligand activin A, a paracrine signaling factor whose activities span tumor microenvironment remodeling, immune modulation, neuroprotection, and reproductive endocrinology [#1, #7, #15, #23]. Across diverse cancers, secreted INHBA/activin A engages SMAD2/3 signaling to activate cancer-associated fibroblasts and drive collagen/ECM deposition, proliferation, migration, and invasion [#3, #5, #19]; INHBA-positive CAFs induce PD-L1 in a SMAD2-dependent autocrine loop and promote regulatory T cell differentiation, while tumor-intrinsic INHBA suppresses IFN-γ signaling to reduce CXCL9/CXCL10-driven effector T cell infiltration—effects reversed by activin A neutralizing antibodies [#7, #15]. INHBA further promotes macrophage M2 polarization, in part through SMAD2/TGF-β-driven CCL2 induction, integrating it into a broader immunosuppressive program [#4, #30, #33]. Beyond classical SMAD signaling, INHBA acts through physical partners: it interacts with integrin ITGA6 to activate MAPK signaling, with CTPS1 to block SMURF1-mediated ubiquitination and stabilize pyrimidine metabolism for gemcitabine resistance, and serves as a required downstream mediator of COL10A1- and THBS2-driven PI3K/AKT signaling [#18, #20, #31, #32]. INHBA expression is tightly controlled transcriptionally by SPI1, C/EBPβ, GLI1, BHLHE40 and KAT8-dependent epigenetics, and post-transcriptionally by miRNAs (miR-146a, miR-130b-3p, miR-204-5p) and the m6A reader IGF2BP1/HuR axis [#4, #12, #13, #14, #16, #17, #29, #30, #33]. In the nervous system, a BDNF→synaptic NMDAR→nuclear calcium axis upregulates Inhba, and the resulting activin A dampens extrasynaptic NMDAR-mediated calcium influx to confer neuroprotection against excitotoxicity and ischemic damage [#1 corrected to #1, #1]. In the brain, this neuroprotective role is established by [#1] (developmental compensation) and the BDNF-driven axis [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that the inhibin β-A subunit has distinct, non-redundant in vivo functions whose appropriate spatiotemporal expression—not just protein identity—determines developmental outcomes, by testing whether the β-B subunit could functionally substitute.\",\n      \"evidence\": \"Targeted knock-in replacing the Inhba mature coding region with Inhbb in mice, with phenotypic rescue analysis\",\n      \"pmids\": [\"10932194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the molecular receptor/effector differences between β-A and β-B\", \"Does not address adult/cancer functions\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"First linked INHBA/activin A to oncogenic proliferation and showed its expression is epigenetically controlled, framing INHBA as a tumor-promoting secreted factor.\",\n      \"evidence\": \"siRNA knockdown, recombinant activin A, follistatin inhibition, and DNA-methylation/HDAC inhibitor treatment in esophageal adenocarcinoma cell lines\",\n      \"pmids\": [\"19240652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation\", \"Downstream signaling pathway not defined\", \"Specific promoter regulatory elements not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a neuroprotective signaling axis, showing activity-dependent Inhba induction restrains pathological extrasynaptic NMDAR signaling.\",\n      \"evidence\": \"Calcium imaging, synaptic/extrasynaptic NMDAR pharmacology, inhba siRNA, recombinant activin A, and an in vivo mouse stroke model\",\n      \"pmids\": [\"26279570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/effector mechanism by which activin A reduces extrasynaptic NMDAR flux not resolved\", \"Human relevance not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed INHBA as a functional downstream node of miR-146a controlling macrophage polarization, connecting INHBA to immune-cell programming.\",\n      \"evidence\": \"3'-UTR luciferase reporter, miRNA gain/loss-of-function, and INHBA rescue with macrophage polarization markers and cytokine readouts\",\n      \"pmids\": [\"27541693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how INHBA signals into macrophages\", \"In vivo confirmation absent\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified INHBA as a paracrine driver of CAF activation downstream of adrenergic stress signaling, defining its role in tumor stroma remodeling.\",\n      \"evidence\": \"Restraint-stress in vivo cancer models, β-blocker pharmacology, INHBA shRNA/siRNA, and CAF/collagen marker imaging\",\n      \"pmids\": [\"28814667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on fibroblasts not identified here\", \"Downstream SMAD requirement defined in later work\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated INHBA-driven stromal activation and tumor growth require SMAD2 and that INHBA sustains active TGF-β signaling in cancer cells.\",\n      \"evidence\": \"INHBA shRNA in ovarian and gastric cancer cells, Smad2 inhibition, xenografts, and TGF-β pathway Western blots\",\n      \"pmids\": [\"31827640\", \"30963572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies\", \"Receptor complex engaged not directly identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded INHBA's immunomodulatory mechanism, showing INHBA+ CAFs induce PD-L1 via autocrine SMAD2 and drive Treg differentiation, with activin A neutralization as a therapeutic strategy.\",\n      \"evidence\": \"INHBA knockdown in ovarian CAFs, CAF/T cell co-culture, recombinant activin A, and anti-activin A neutralizing antibody in vivo with patient tissue analysis\",\n      \"pmids\": [\"38360876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contact molecule mediating Treg differentiation not identified\", \"Generality across tumor types not tested here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected INHBA to therapy resistance and metabolic reprogramming, showing stromal- and tumor-intrinsic INHBA supports glycolysis and lapatinib resistance in HER2+ breast cancer.\",\n      \"evidence\": \"siRNA knockdown, metabolic profiling, lapatinib sensitivity assays, and PEAK1-dependent conditioned-medium secretome analysis in MSCs/CAFs\",\n      \"pmids\": [\"35248133\", \"34239043\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between INHBA and metabolic switch not defined\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established INHBA as a regulator of ovarian granulosa cell steroidogenesis and follicular hormone output.\",\n      \"evidence\": \"INHBA overexpression/knockdown in sheep granulosa cells with hormone ELISA and TGF-β gene expression analysis\",\n      \"pmids\": [\"34537472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of steroidogenic gene control not defined\", \"Single species, in vitro\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined multiple post-transcriptional and transcriptional control layers (circTHBS1/miR-204-5p/HuR, BHLHE40) and pharmacological suppression (metformin) governing INHBA-driven TGF-β/PI3K-Akt and Hippo signaling.\",\n      \"evidence\": \"RNA pulldown, RIP, luciferase reporters, metformin treatment, cell-cycle/senescence assays, and Verteporfin Hippo inhibition across colon and gastric cancer models\",\n      \"pmids\": [\"35338119\", \"35236827\", \"38588888\", \"35689549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BHLHE40 regulation lacks direct ChIP\", \"Causal hierarchy among co-regulated pathways not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established m6A-dependent stabilization of INHBA mRNA by IGF2BP1 and microRNA control of an INHBA-angiogenesis axis, linking RNA regulation to downstream Smad2/3 and IL-8 signaling.\",\n      \"evidence\": \"RIP-seq, RNA pulldown, m6A PCR, RNA stability assays, BTYNB inhibitor (IGF2BP1), and miR-130b-3p mimics/inhibitors with INHBA siRNA epistasis in endothelial cells and in vivo ischemia models\",\n      \"pmids\": [\"37644505\", \"37097749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor-level events downstream of activin A in endothelium not fully mapped\", \"Cross-talk between BMP and TGF-β arms not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed INHBA's direct physical partners and non-SMAD effector routes—ITGA6/MAPK, CTPS1 stabilization for pyrimidine metabolism, and IFN-γ pathway suppression—broadening its mechanism beyond canonical ligand signaling.\",\n      \"evidence\": \"Co-IP/Co-IF (ITGA6), IP-MS and ubiquitination assays (CTPS1), and gain/loss-of-function with anti-activin A antibody (garetosmab) plus anti-PD-L1 across multiple mouse tumor models\",\n      \"pmids\": [\"41799510\", \"41239468\", \"39223366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether intracellular CTPS1 binding reflects non-secreted INHBA pool not resolved\", \"Structural basis of partner interactions unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped transcriptional regulators (GLI1 feedback loop, KAT8 epigenetic axis, SPI1) and paracrine FAP+ stromal sources controlling INHBA in cancer and vascular senescence.\",\n      \"evidence\": \"ChIP and reporter assays (GLI1, SPI1), CRISPR multi-omics (KAT8), and FAP+ cell isolation with ELISA/SMAD2/3 readouts\",\n      \"pmids\": [\"38676428\", \"41445196\", \"40132395\", \"39615112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each regulator in physiological tissue unknown\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reinforced INHBA's neuroprotective and reproductive roles, identifying its suppression in neurodegeneration and its function in thecal cell proliferation in PCOS.\",\n      \"evidence\": \"esNMDAR activation with RNA-seq and Huntington's disease mouse model rescue (memantine/FP802); spatial transcriptomics with Inhba/Smad2/E2f4 knockdown in a PCOS mouse model\",\n      \"pmids\": [\"41339520\", \"40831751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting esNMDAR to Inhba transcriptional repression not detailed\", \"Human relevance of PCOS axis not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified additional INHBA-dependent oncogenic signaling partners (COL10A1, THBS2 via FAK/PI3K/AKT) and a role in valvular osteogenic calcification, extending its mechanistic reach.\",\n      \"evidence\": \"Co-IP and INHBA-knockdown rescue with PI3K/AKT/FAK readouts in prostate cancer; INHBA siRNA with osteogenic induction and single-cell RNA-seq in valvular interstitial cells\",\n      \"pmids\": [\"39656597\", \"41810913\", \"42059080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"THBS2-INHBA interaction inferred without direct Co-IP\", \"Mechanism of INHBA in calcification not molecularly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor complexes and structural determinants linking secreted activin A versus intracellular INHBA interactions (CTPS1, integrins, collagens) to the divergent SMAD, MAPK, and PI3K/AKT outputs remain undefined, as does how a single ligand selects among context-specific effector programs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of INHBA-partner complexes\", \"Receptor selection mechanism across tissues unknown\", \"Distinction between secreted ligand and intracellular binding pools unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 7, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 19, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 7, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 7, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 13, 18]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTPS1\", \"ITGA6\", \"COL10A1\", \"THBS2\", \"IGF2BP1\", \"SMURF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}