{"gene":"INHBB","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1989,"finding":"The INHBB gene encodes a 407-amino acid precursor with a prepro region of 292 amino acids followed by the mature 115-amino acid C-terminal domain. Mammalian cells transfected with a βB-subunit expression plasmid secreted an activin B homodimer (~22 kDa). Co-expression of βA and βB subunits produced all three activin isoforms (A, AB, and B). Purified activin B stimulated FSH release in vitro and induced hemoglobin accumulation in K562 cells with potency (ED50 ~2 ng/ml) indistinguishable from activin A.","method":"cDNA/genomic cloning, transfection and secretion assay, in vitro pituitary FSH assay, K562 cell differentiation assay","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted protein from cDNA, multiple in vitro functional assays","pmids":["2575216"],"is_preprint":false},{"year":1986,"finding":"Human ovarian inhibin consists of two forms sharing a common alpha subunit covalently linked to one of two distinct beta subunits (βA or βB). The βB subunit sequence (INHBB) is highly conserved with its porcine equivalent, differing at only one of 232 positions.","method":"cDNA cloning and nucleotide sequencing","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — direct sequence determination from cDNA clones, foundational structural characterization","pmids":["3754442"],"is_preprint":false},{"year":1991,"finding":"Activin B (the INHBB homodimer) binds to the cloned activin receptor (a predicted transmembrane serine/threonine kinase) expressed in COS cells with an affinity of 180 pM, and can compete with activin A for receptor binding.","method":"Expression cloning, 125I-activin A binding competition assay in COS cell transfectants","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — direct radioligand binding assay with competition, receptor cloning","pmids":["1646080"],"is_preprint":false},{"year":2000,"finding":"Replacement of the mature protein-coding region of Inhba with Inhbb (creating the InhbaBK knock-in allele) rescued Inhba-null craniofacial phenotypes (whisker, palate, tooth defects), demonstrating functional compensation between activin A and activin B within the TGF-β superfamily when expressed from the same locus. However, novel somatic, testicular, genital, and hair growth phenotypes emerged, indicating distinct dosage and bioactivity differences between the two ligands.","method":"Gene targeting (knock-in), mouse genetics, phenotypic analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via knock-in allele with multiple phenotypic readouts, replaces endogenous locus","pmids":["10932194"],"is_preprint":false},{"year":2000,"finding":"Activin βC subunit (encoded by a related gene) can form heterodimers with activin βA and βB subunits in vitro (activin AC and BC), but cannot dimerize with the inhibin alpha subunit. This establishes that INHBB (βB) is capable of forming novel heterodimeric activin complexes beyond the canonical activin B homodimer.","method":"In vitro dimerization assay, antibody localization, co-immunoprecipitation","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 1/2 — in vitro reconstitution of dimerization, but functional consequence of BC heterodimer not established","pmids":["11134153"],"is_preprint":false},{"year":2004,"finding":"Activin B (INHBB homodimer) and activin AB signal through the type I receptor serine/threonine kinase ALK7, in combination with ActRIIA, to mediate insulin secretion from pancreatic β-cells. This receptor preference distinguishes activin B from activin A (which preferentially uses ALK4). The differential signaling depends on the homo- or heterodimeric assembly of activin isoforms.","method":"Receptor binding assay, reporter gene assay, pancreatic β-cell (MIN6) insulin secretion assay, receptor co-expression experiments","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1/2 — multiple receptor binding and functional assays, cell-based signaling validation","pmids":["15196700"],"is_preprint":false},{"year":2008,"finding":"Activin B (INHBB homodimer) was identified in human and mouse serum by affinity purification using soluble ActRII and ActRIIB, confirming it circulates as an endocrine factor. Activin B bound both ActRII and ActRIIB and, like myostatin, inhibited myoblast-to-myotube differentiation in vitro.","method":"Affinity purification from serum, mass spectrometry proteomics, in vitro binding assay, myoblast differentiation assay","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1/2 — proteomic identification from native serum combined with functional validation","pmids":["18927237"],"is_preprint":false},{"year":2012,"finding":"Activin B (encoded by Inhbb) induces phosphorylation of Smad1/5/8 in human hepatoma-derived cells and, synergistically with IL-6/STAT-3 signaling, up-regulates hepcidin expression. The effect on hepcidin is mediated through BMP signaling, most likely via activin receptor-like kinase 3 (ALK3). Inhbb mRNA is dramatically induced in mouse liver after LPS challenge, preceding Smad1/5/8 phosphorylation and hepcidin (Hamp) mRNA increases.","method":"In vivo LPS challenge, Smad1/5/8 phosphorylation assay, qPCR, ALK3 inhibitor treatment, primary hepatocyte assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (in vivo, cell-based, inhibitor), mechanistic pathway placement","pmids":["22611157"],"is_preprint":false},{"year":2013,"finding":"Elevated activin B (among other activins) reduces skeletal muscle mass and function by stimulating the ActRIIB pathway, leading to increased transcription of atrophy-related ubiquitin ligases and decreased Akt/mTOR-mediated protein synthesis. Activin B was identified as one of the most potent negative regulators of muscle mass, and the resulting muscle wasting is fully reversible.","method":"rAAV6-mediated overexpression in mice, ActRIIB signaling assays, ubiquitin ligase expression assays, Akt/mTOR pathway analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — in vivo gain-of-function with pathway analysis, multiple molecular readouts","pmids":["24378873"],"is_preprint":false},{"year":2015,"finding":"RNAi-mediated knockdown of INHBB in mouse granulosa cells arrests cells in G1 phase, increases apoptosis, and decreases estradiol and progesterone production. Mechanistically, INHBB knockdown downregulated Cyclin D1, Cyclin E, and Bcl2 protein expression while upregulating Bax, and reduced mRNA levels of CYP19A1 and CYP11A1, placing INHBB as a regulator of cell cycle progression and steroidogenesis in granulosa cells.","method":"RNAi knockdown, flow cytometry, Western blot, ELISA, qRT-PCR","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2/3 — loss-of-function with multiple molecular readouts, single lab","pmids":["26063610"],"is_preprint":false},{"year":2017,"finding":"Menin represses Inhbb expression by facilitating recruitment of Ezh2 to the Inhbb promoter via an indirect mechanism involving Akt phosphorylation, resulting in H3K27me3 repressive marks at the Inhbb locus. Loss of Menin leads to reduced H3K27me3 at the Inhbb locus and increased activin B expression both in vitro and in vivo in insulinoma models.","method":"ChIP assay, H3K27me3 chromatin immunoprecipitation, Menin knockout cell lines and animal models, Akt inhibitor experiments","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and epigenetic assays with in vivo validation, single lab","pmids":["28215965"],"is_preprint":false},{"year":2020,"finding":"Sox9 directly binds to the INHBB enhancer and induces INHBB expression in hepatoma cells, promoting secretion of activin B. Secreted activin B in turn activates surrounding hepatic stellate cells through activin B/Smad signaling, promoting liver fibrosis and HCC metastasis. Inhibition of activin B/Smad signaling attenuated peri-tumoral fibrosis and metastasis.","method":"Gain- and loss-of-function experiments, ChIP assay (Sox9 binding to INHBB enhancer), orthotopic HCC tumor model, Smad signaling inhibition","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct Sox9-INHBB enhancer binding, in vivo validation, mechanistic pathway placement","pmids":["33246092"],"is_preprint":false},{"year":2021,"finding":"Tubular epithelial cell-derived INHBB (activin B) promotes renal fibrosis by activating surrounding interstitial fibroblasts in a paracrine manner through activin B/Smad signaling. Ectopic expression of INHBB in tubular cells initiates interstitial fibrosis in vivo, while INHBB inhibition blocks fibroblast activation and ameliorates fibrosis from ureteral obstruction or ischemia-reperfusion injury. Upregulation of INHBB in injured tubular cells depends on transcription factor Sox9.","method":"In vivo INHBB inhibition and ectopic overexpression in mouse fibrosis models, in vitro overexpression in tubular cells, Smad signaling assays","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gain- and loss-of-function, paracrine mechanism with pathway placement, single lab","pmids":["34543458"],"is_preprint":false},{"year":2022,"finding":"A missense variant in INHBB (p.Met360Thr/p.Met364Thr in mice) disrupts activin B biosynthesis in vitro without affecting inhibin B production, reducing circulating activin B levels. In knock-in mice, this variant increased testis size, Sertoli cell number, and round spermatid number without affecting fertility, demonstrating that activin B specifically regulates testis cell composition independent of FSH.","method":"CRISPR/Cas9 knock-in mouse model, in vitro biosynthesis assay, serum hormone analysis, histomorphometry","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR knock-in with in vitro biosynthesis validation, multiple phenotypic readouts","pmids":["35022746"],"is_preprint":false},{"year":2023,"finding":"INHBB knockdown in human endometrial stromal cells suppresses ADCY1-mediated cAMP production and downstream cAMP signaling, thereby attenuating decidualization. RNA-seq identified INHBB-ADCY1 as a mechanistic axis, and a positive correlation between INHBB and ADCY1 expression was confirmed in endometria from recurrent implantation failure patients.","method":"siRNA knockdown, RNA-seq, cAMP analogue rescue experiment, qRT-PCR, Pearson correlation analysis","journal":"Journal of assisted reproduction and genetics","confidence":"Medium","confidence_rationale":"Tier 2/3 — loss-of-function with pathway rescue, but pathway placement relies on correlation and single knockdown approach","pmids":["36913138"],"is_preprint":false},{"year":2025,"finding":"INHBB knockdown in colorectal cancer cells reduces migration, invasion, and hepatic metastasis in vivo by attenuating TGF-β/Smad2/3/Smad4 signaling (decreased Smad2/3 phosphorylation), reversing EMT (E-cadherin upregulation, N-cadherin and vimentin downregulation), and sensitizing cells to anoikis.","method":"siRNA knockdown in HCT116/Caco-2 cells, Western blot for Smad phosphorylation, EMT markers and anoikis assay, in vivo spleen injection xenograft model","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple molecular pathway readouts and in vivo validation","pmids":["41380489"],"is_preprint":false}],"current_model":"INHBB encodes the inhibin βB subunit, which homodimerizes to form activin B (or heterodimerizes with βA to form activin AB) and signals through type II activin receptors (ActRIIA/IIB) and type I receptors ALK4 or ALK7 to activate Smad2/3 or, in hepatic contexts, Smad1/5/8 pathways; its transcription is controlled by Sox9 (via direct enhancer binding) and repressed by Menin through Akt/Ezh2-mediated H3K27me3 marks, while its biological roles include regulation of FSH secretion, skeletal muscle mass (via ActRIIB/atrogene pathway), hepcidin induction in inflammation (via ALK3/Smad1/5/8), granulosa cell cycle and steroidogenesis, renal and hepatic fibrosis (via paracrine Smad signaling to fibroblasts/stellate cells), endometrial decidualization (via ADCY1/cAMP), and testis cell composition."},"narrative":{"teleology":[{"year":1986,"claim":"Identification of INHBB as a distinct inhibin β subunit gene established that inhibin exists in two forms (βA and βB) sharing a common alpha chain, laying the molecular foundation for understanding activin/inhibin diversity.","evidence":"cDNA cloning and sequencing of the human βB subunit from ovarian cDNA libraries","pmids":["3754442"],"confidence":"High","gaps":["No functional assay for the βB subunit alone","Dimerization partners and receptor not yet identified"]},{"year":1989,"claim":"Reconstitution of activin B from cloned INHBB cDNA demonstrated that the βB subunit homodimerizes to form a bioactive ligand indistinguishable from activin A in stimulating FSH release and erythroid differentiation, establishing activin B as a functional TGF-β superfamily member.","evidence":"Transfection/secretion in mammalian cells, pituitary FSH bioassay, K562 hemoglobin induction assay","pmids":["2575216"],"confidence":"High","gaps":["Receptor identity unknown","In vivo relevance not tested"]},{"year":1991,"claim":"Demonstration that activin B binds a cloned transmembrane serine/threonine kinase receptor with subnanomolar affinity and competes with activin A resolved how both activin isoforms converge on a shared receptor system.","evidence":"Radioligand binding and competition assay in COS cells expressing cloned activin receptor","pmids":["1646080"],"confidence":"High","gaps":["Type I receptor specificity not defined","Intracellular signaling cascade downstream of binding unknown"]},{"year":2000,"claim":"A knock-in replacing Inhba coding sequence with Inhbb showed that activin B can rescue activin A-dependent craniofacial development but cannot fully substitute in testicular, genital, and hair phenotypes, establishing both overlapping and distinct biological activities for the two activin isoforms in vivo.","evidence":"Gene targeting knock-in in mice, systematic phenotypic analysis","pmids":["10932194"],"confidence":"High","gaps":["Molecular basis of differential bioactivity not resolved","Whether differences reflect receptor affinity or tissue availability unclear"]},{"year":2004,"claim":"Identification of ALK7 as a preferential type I receptor for activin B (versus ALK4 for activin A) and demonstration that activin B stimulates insulin secretion through ALK7/ActRIIA provided a mechanistic basis for isoform-specific signaling.","evidence":"Receptor binding assays, reporter gene assays, and insulin secretion assays in MIN6 pancreatic β-cells","pmids":["15196700"],"confidence":"High","gaps":["Structural basis for ALK7 selectivity not determined","In vivo relevance of ALK7-mediated insulin secretion not confirmed"]},{"year":2008,"claim":"Affinity-purification of activin B from native human and mouse serum confirmed its status as a circulating endocrine factor and revealed that it, like myostatin, inhibits myoblast differentiation, expanding its role beyond reproductive endocrinology to muscle biology.","evidence":"Soluble ActRII/ActRIIB affinity purification from serum, mass spectrometry, myoblast differentiation assay","pmids":["18927237"],"confidence":"High","gaps":["In vivo muscle mass effects not yet demonstrated","Relative contribution versus myostatin unknown"]},{"year":2012,"claim":"Activin B was shown to induce hepcidin via Smad1/5/8 phosphorylation through ALK3 in hepatocytes, synergizing with IL-6/STAT3, establishing a non-canonical BMP-like signaling mode for activin B in inflammatory iron regulation.","evidence":"LPS challenge in mice, Smad1/5/8 phosphorylation assays, ALK3 inhibitor studies, primary hepatocyte assays","pmids":["22611157"],"confidence":"High","gaps":["Whether ALK3 engagement is direct or requires co-receptors not resolved","Contribution relative to BMP6 in hepcidin induction in vivo unclear"]},{"year":2013,"claim":"In vivo overexpression of activin B in muscle demonstrated that it is a potent inducer of atrophy through ActRIIB-mediated upregulation of atrogenes and suppression of Akt/mTOR protein synthesis, confirming a direct catabolic role in skeletal muscle.","evidence":"rAAV6-mediated overexpression in mouse muscle, ubiquitin ligase and Akt/mTOR pathway analysis","pmids":["24378873"],"confidence":"High","gaps":["Endogenous activin B contribution to cachexia not proven by loss-of-function","Relative potency versus activin A in muscle wasting not quantified"]},{"year":2017,"claim":"Epigenetic regulation of INHBB transcription was resolved: Menin recruits Ezh2 via Akt-dependent phosphorylation to deposit H3K27me3 repressive marks at the Inhbb locus, and Menin loss de-represses activin B in insulinoma, linking tumor suppressor pathways to activin B expression.","evidence":"ChIP for H3K27me3 and Ezh2, Menin-knockout cell lines, Akt inhibitor experiments, in vivo insulinoma models","pmids":["28215965"],"confidence":"Medium","gaps":["Whether Menin-Ezh2 regulation of INHBB operates outside pancreatic neuroendocrine tissue not established","Direct versus indirect Akt-Ezh2 link not fully dissected"]},{"year":2020,"claim":"Sox9 was identified as a direct transcriptional activator of INHBB via enhancer binding, and secreted activin B was shown to activate hepatic stellate cells through Smad signaling to promote fibrosis and metastasis, establishing a Sox9-INHBB-Smad paracrine axis in the liver tumor microenvironment.","evidence":"ChIP for Sox9 at INHBB enhancer, orthotopic HCC model, Smad signaling inhibition","pmids":["33246092"],"confidence":"Medium","gaps":["Whether Sox9 regulation of INHBB is tissue-general or liver-specific not determined","Identity of specific Smad pathway (Smad2/3 vs Smad1/5/8) in stellate cell activation not resolved"]},{"year":2021,"claim":"Extension of the paracrine fibrosis paradigm to kidney showed that tubular epithelial INHBB activates interstitial fibroblasts through activin B/Smad signaling, with INHBB inhibition ameliorating renal fibrosis, generalizing the injured-epithelium-to-fibroblast paracrine mechanism.","evidence":"In vivo INHBB overexpression and inhibition in UUO and ischemia-reperfusion injury mouse models, Smad signaling assays","pmids":["34543458"],"confidence":"Medium","gaps":["Specific Smad isoform usage in renal fibroblasts not determined","Whether follistatin or other endogenous antagonists modulate this axis in vivo not tested"]},{"year":2022,"claim":"A missense INHBB variant that selectively disrupts activin B (but not inhibin B) biosynthesis increased Sertoli and spermatid cell numbers in knock-in mice without affecting fertility, disentangling activin B from inhibin B function and demonstrating a specific role for activin B in testis cell composition.","evidence":"CRISPR/Cas9 knock-in mice, in vitro biosynthesis assay, serum hormone analysis, histomorphometry","pmids":["35022746"],"confidence":"Medium","gaps":["Mechanism by which reduced activin B increases Sertoli cell number not identified","Whether this variant affects activin AB heterodimerization not tested"]},{"year":2023,"claim":"INHBB was linked to endometrial decidualization through an ADCY1/cAMP axis, where INHBB knockdown suppressed cAMP production and downstream decidualization markers, connecting activin B to non-Smad signaling in reproductive biology.","evidence":"siRNA knockdown in human endometrial stromal cells, RNA-seq, cAMP analogue rescue","pmids":["36913138"],"confidence":"Medium","gaps":["Whether activin B directly upregulates ADCY1 transcription or acts indirectly not resolved","Receptor and Smad-independence of this pathway not formally tested"]},{"year":2025,"claim":"INHBB was shown to promote colorectal cancer metastasis by sustaining Smad2/3/Smad4 phosphorylation, EMT, and anoikis resistance, extending the pro-metastatic role of activin B signaling beyond HCC to additional gastrointestinal cancers.","evidence":"siRNA knockdown in CRC cell lines, Smad phosphorylation and EMT marker analysis, splenic injection xenograft hepatic metastasis model","pmids":["41380489"],"confidence":"Medium","gaps":["Whether the effect is autocrine or paracrine in the metastatic niche not distinguished","Activin B-specific versus pan-activin contribution not dissected"]},{"year":null,"claim":"The structural basis for activin B's selective engagement of ALK7 versus ALK4, the relative in vivo contribution of activin B versus other ActRIIB ligands (myostatin, GDF11) in muscle wasting, and the mechanism linking activin B to ADCY1/cAMP signaling independently of canonical Smad pathways remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of activin B in complex with ALK7","No conditional Inhbb knockout dissecting endogenous activin B roles across tissues","Smad-independent signaling mechanisms of activin B poorly characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,5,6,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,14]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,6,7,11,12]}],"pathway":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,7,8,11,12,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,13]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[9,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,12,15]}],"complexes":["Activin B homodimer (βB-βB)","Activin AB heterodimer (βA-βB)","Inhibin B heterodimer (α-βB)"],"partners":["INHBA","INHA","ACVR2A","ACVR2B","ACVR1C","ACVR1B","SOX9","MEN1"],"other_free_text":[]},"mechanistic_narrative":"INHBB encodes the inhibin βB subunit, which homodimerizes to form activin B or heterodimerizes with βA to form activin AB; these TGF-β superfamily ligands signal through type II activin receptors (ActRIIA/ActRIIB) and type I receptors ALK4/ALK7 to activate Smad2/3, or, in hepatic contexts, ALK3 to activate Smad1/5/8 [PMID:2575216, PMID:15196700, PMID:22611157]. Activin B circulates as an endocrine factor and acts as a potent regulator of FSH secretion, skeletal muscle mass (via ActRIIB/atrogene induction), inflammation-induced hepcidin expression, and testis cell composition [PMID:18927237, PMID:24378873, PMID:22611157, PMID:35022746]. In paracrine settings, INHBB-derived activin B produced by injured epithelial cells activates fibroblasts and stellate cells through Smad signaling to promote renal and hepatic fibrosis, and drives EMT and metastasis in colorectal and hepatocellular carcinoma models [PMID:34543458, PMID:33246092, PMID:41380489]. Transcription of INHBB is positively regulated by Sox9 via direct enhancer binding and repressed by Menin through Akt/Ezh2-mediated H3K27me3 deposition [PMID:33246092, PMID:28215965]."},"prefetch_data":{"uniprot":{"accession":"P09529","full_name":"Inhibin beta B chain","aliases":["Activin beta-B chain"],"length_aa":407,"mass_kda":45.1,"function":"Inhibins and activins inhibit and activate, respectively, the secretion of follitropin by the pituitary gland. 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. Inhibins appear to oppose the functions of activins Activin B is a dimer of alpha and beta-B that plays a role in several essential biological processes including embryonic development, stem cell maintenance and differentiation, haematopoiesis, cell proliferation and wound healing (PubMed:22611157, PubMed:15196700). Signals through type I receptor ACVR1C, abundantly expressed in pancreatic beta cells, and type II receptors like ACVR2A or BMPR2 (PubMed:35643319). Upon ligand binding, these receptors phosphorylate intracellular signaling mediators SMAD2 and SMAD3, which form a complex with SMAD4, translocate to the nucleus, and regulate gene expression (PubMed:15196700). Plays a crucial role in the induction of hepcidin by inflammation through activation of ACVR1C and subsequent phosphorylation of SMAD1/5/8 (PubMed:22611157). Regulates adipocyte lipid metabolism by decreasing non-esterified fatty acids and glycerol release and increases intracellular triglyceride content (By similarity). Stimulates wound healing by promoting cell migration and hair follicle regeneration through the JNK and ERK signaling pathways downstream of RHOA (By similarity) Inhibin B is a dimer of alpha and beta-B that plays a crucial role in the regulation of the reproductive system by inhibiting the secretion of follicle-stimulating hormone (FSH) from the anterior pituitary gland. Thereby, maintains reproductive homeostasis in both males and females. Acts as a more potent suppressor of FSH release than inhibin A (By similarity). Functions as competitive receptor antagonist binding activin type II receptors with high affinity in the presence of the TGF-beta type III coreceptor/TGFBR3L (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P09529/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INHBB","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/INHBB","total_profiled":1310},"omim":[{"mim_id":"612031","title":"INHIBIN, BETA E; INHBE","url":"https://www.omim.org/entry/612031"},{"mim_id":"601788","title":"MYOSTATIN; MSTN","url":"https://www.omim.org/entry/601788"},{"mim_id":"600963","title":"SIX HOMEOBOX 5; SIX5","url":"https://www.omim.org/entry/600963"},{"mim_id":"276400","title":"TWINNING, DIZYGOTIC","url":"https://www.omim.org/entry/276400"},{"mim_id":"228300","title":"HYPOGONADOTROPIC HYPOGONADISM 23 WITH OR WITHOUT ANOSMIA; HH23","url":"https://www.omim.org/entry/228300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":49.6},{"tissue":"breast","ntpm":42.2}],"url":"https://www.proteinatlas.org/search/INHBB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P09529","domains":[{"cath_id":"2.10.90.10","chopping":"76-84_291-407","consensus_level":"high","plddt":81.1727,"start":76,"end":407},{"cath_id":"2.60.120.970","chopping":"141-283","consensus_level":"high","plddt":82.8344,"start":141,"end":283}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09529","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09529-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09529-F1-predicted_aligned_error_v6.png","plddt_mean":73.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INHBB","jax_strain_url":"https://www.jax.org/strain/search?query=INHBB"},"sequence":{"accession":"P09529","fasta_url":"https://rest.uniprot.org/uniprotkb/P09529.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09529/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09529"}},"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,"source_track":"pubmed_title"},{"pmid":"26063610","id":"PMC_26063610","title":"RNAi-mediated knockdown of INHBB increases apoptosis and inhibits steroidogenesis in mouse granulosa cells.","date":"2015","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/26063610","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33246092","id":"PMC_33246092","title":"Sox9/INHBB axis-mediated crosstalk between the hepatoma and hepatic stellate cells promotes the metastasis of hepatocellular carcinoma.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/33246092","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34543458","id":"PMC_34543458","title":"Tubule-derived INHBB promotes interstitial fibroblast activation and renal fibrosis.","date":"2021","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34543458","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28215965","id":"PMC_28215965","title":"Menin regulates Inhbb expression through an Akt/Ezh2-mediated H3K27 histone modification.","date":"2017","source":"Biochimica et biophysica acta. 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\"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vivo genetic epistasis/rescue with multiple phenotypic readouts; highly cited foundational study\",\n      \"pmids\": [\"10932194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNAi-mediated knockdown of INHBB in mouse granulosa cells arrests cells in G1 phase, increases apoptosis (downregulating Cyclin D1, Cyclin E, Bcl2; upregulating Bax), and decreases estradiol and progesterone production by reducing CYP19A1 and CYP11A1 expression, establishing INHBB as a regulator of granulosa cell survival, cell cycle progression, and steroidogenesis.\",\n      \"method\": \"RNAi knockdown in primary mouse granulosa cells; flow cytometry, Western blot, ELISA, qRT-PCR\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single lab; clean KD with defined cellular phenotype\",\n      \"pmids\": [\"26063610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Menin represses Inhbb expression by binding to the Inhbb promoter and facilitating Ezh2 recruitment (via Akt-phosphorylation-dependent indirect interaction), promoting H3K27me3 repressive marks at the Inhbb locus; loss of Menin leads to reduced H3K27me3 and upregulation of activin B (INHBB).\",\n      \"method\": \"Menin knockout mouse model and cell lines; ChIP for H3K27me3 and Menin binding; Akt phosphorylation analysis; in vivo and in vitro INHBB expression measurement\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, KO model, in vitro) from a single lab\",\n      \"pmids\": [\"28215965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sox9 directly binds the INHBB enhancer to induce INHBB expression in hepatoma cells; secreted activin B (INHBB homodimer) then activates surrounding hepatic stellate cells via activin B/Smad signaling, promoting liver fibrosis and HCC metastasis. Inhibition of activin B/Smad signaling attenuated fibrosis and metastasis.\",\n      \"method\": \"Gain- and loss-of-function experiments; ChIP/enhancer binding assay; orthotopic HCC mouse model; Smad signaling inhibition\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including in vivo model and mechanistic signaling inhibition\",\n      \"pmids\": [\"33246092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In renal tubular epithelial cells (TECs), Sox9 upregulates INHBB expression; secreted activin B (INHBB homodimer) acts in a paracrine manner to activate interstitial fibroblasts through activin B/Smad signaling, driving renal fibrosis. In vivo INHBB inhibition blocked fibroblast activation and ameliorated fibrosis, while TEC-specific INHBB overexpression initiated fibrosis.\",\n      \"method\": \"In vivo UUO and ischemia-reperfusion injury models; INHBB overexpression/inhibition; in vitro fibroblast co-culture; Smad signaling analysis\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo and in vitro methods with defined mechanistic pathway placement\",\n      \"pmids\": [\"34543458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A human INHBB variant (p.Met360Thr; mouse equivalent p.Met364Thr) generated by CRISPR/Cas9 reduces circulating activin B levels without affecting FSH, increases testis size with more Sertoli cells and round spermatids, and in vitro biosynthesis assays confirm this variant (and p.Thr105Met) disrupts activin B assembly/secretion, establishing that INHBB integrity is required for normal activin B production and testis composition.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse; serum hormone analysis; in vitro biosynthesis assay; histomorphometry\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — in vivo knock-in with multiple readouts and in vitro biosynthesis validation\",\n      \"pmids\": [\"35022746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INHBB knockdown in endometrial stromal cells suppresses ADCY1 expression, reducing cAMP production and cAMP-mediated signaling, thereby impairing decidualization; positive correlation between INHBB and ADCY1 expression was confirmed, placing INHBB upstream of the ADCY1/cAMP axis in decidualization.\",\n      \"method\": \"siRNA-mediated INHBB knockdown in human endometrial stromal cells; RNA-seq; RT-qPCR; immunofluorescence; Pearson correlation analysis\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq plus siRNA knockdown with defined signaling pathway and clinical correlation\",\n      \"pmids\": [\"36913138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INHBB knockdown in colorectal cancer cells attenuates TGF-β/Smad2/3/Smad4 signaling (reduced Smad2/3 phosphorylation), reverses EMT (E-cadherin up, N-cadherin and vimentin down), and sensitizes cells to anoikis, reducing hepatic metastasis in a xenograft mouse model.\",\n      \"method\": \"siRNA knockdown in HCT116/Caco-2 cells; Western blot for Smad phosphorylation and EMT markers; anoikis assay; in vivo spleen injection xenograft model\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo methods with defined signaling readouts\",\n      \"pmids\": [\"41380489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KLF10 overexpression in chondrocytes suppresses INHBB expression (and upregulates Acvr1), inhibiting chondrocyte proliferation and migration, identifying KLF10 as a transcriptional repressor of INHBB in chondrocytes.\",\n      \"method\": \"KLF10 overexpression in primary mouse chondrocytes; RNA-seq; qRT-PCR; proliferation and migration assays\",\n      \"journal\": \"Acta histochemica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, overexpression with RNA-seq; no direct demonstration of KLF10 binding to INHBB locus\",\n      \"pmids\": [\"32156482\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INHBB encodes the inhibin βB subunit, which forms activin B homodimers (and inhibin B heterodimers with the α subunit) that signal through activin receptors and Smad pathways to regulate FSH secretion, granulosa cell survival and steroidogenesis, testis composition, endometrial decidualization (via ADCY1/cAMP), and tissue fibrosis (via paracrine activin B/Smad signaling activated downstream of Sox9); its transcription is repressed by Menin through Akt-dependent Ezh2 recruitment and H3K27me3 deposition, and functionally it can partially substitute for the related βA subunit when expressed in the correct spatiotemporal context.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"The INHBB gene encodes a 407-amino acid precursor with a prepro region of 292 amino acids followed by the mature 115-amino acid C-terminal domain. Mammalian cells transfected with a βB-subunit expression plasmid secreted an activin B homodimer (~22 kDa). Co-expression of βA and βB subunits produced all three activin isoforms (A, AB, and B). Purified activin B stimulated FSH release in vitro and induced hemoglobin accumulation in K562 cells with potency (ED50 ~2 ng/ml) indistinguishable from activin A.\",\n      \"method\": \"cDNA/genomic cloning, transfection and secretion assay, in vitro pituitary FSH assay, K562 cell differentiation assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted protein from cDNA, multiple in vitro functional assays\",\n      \"pmids\": [\"2575216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Human ovarian inhibin consists of two forms sharing a common alpha subunit covalently linked to one of two distinct beta subunits (βA or βB). The βB subunit sequence (INHBB) is highly conserved with its porcine equivalent, differing at only one of 232 positions.\",\n      \"method\": \"cDNA cloning and nucleotide sequencing\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct sequence determination from cDNA clones, foundational structural characterization\",\n      \"pmids\": [\"3754442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Activin B (the INHBB homodimer) binds to the cloned activin receptor (a predicted transmembrane serine/threonine kinase) expressed in COS cells with an affinity of 180 pM, and can compete with activin A for receptor binding.\",\n      \"method\": \"Expression cloning, 125I-activin A binding competition assay in COS cell transfectants\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct radioligand binding assay with competition, receptor cloning\",\n      \"pmids\": [\"1646080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Replacement of the mature protein-coding region of Inhba with Inhbb (creating the InhbaBK knock-in allele) rescued Inhba-null craniofacial phenotypes (whisker, palate, tooth defects), demonstrating functional compensation between activin A and activin B within the TGF-β superfamily when expressed from the same locus. However, novel somatic, testicular, genital, and hair growth phenotypes emerged, indicating distinct dosage and bioactivity differences between the two ligands.\",\n      \"method\": \"Gene targeting (knock-in), mouse genetics, phenotypic analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via knock-in allele with multiple phenotypic readouts, replaces endogenous locus\",\n      \"pmids\": [\"10932194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Activin βC subunit (encoded by a related gene) can form heterodimers with activin βA and βB subunits in vitro (activin AC and BC), but cannot dimerize with the inhibin alpha subunit. This establishes that INHBB (βB) is capable of forming novel heterodimeric activin complexes beyond the canonical activin B homodimer.\",\n      \"method\": \"In vitro dimerization assay, antibody localization, co-immunoprecipitation\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro reconstitution of dimerization, but functional consequence of BC heterodimer not established\",\n      \"pmids\": [\"11134153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Activin B (INHBB homodimer) and activin AB signal through the type I receptor serine/threonine kinase ALK7, in combination with ActRIIA, to mediate insulin secretion from pancreatic β-cells. This receptor preference distinguishes activin B from activin A (which preferentially uses ALK4). The differential signaling depends on the homo- or heterodimeric assembly of activin isoforms.\",\n      \"method\": \"Receptor binding assay, reporter gene assay, pancreatic β-cell (MIN6) insulin secretion assay, receptor co-expression experiments\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple receptor binding and functional assays, cell-based signaling validation\",\n      \"pmids\": [\"15196700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Activin B (INHBB homodimer) was identified in human and mouse serum by affinity purification using soluble ActRII and ActRIIB, confirming it circulates as an endocrine factor. Activin B bound both ActRII and ActRIIB and, like myostatin, inhibited myoblast-to-myotube differentiation in vitro.\",\n      \"method\": \"Affinity purification from serum, mass spectrometry proteomics, in vitro binding assay, myoblast differentiation assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — proteomic identification from native serum combined with functional validation\",\n      \"pmids\": [\"18927237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Activin B (encoded by Inhbb) induces phosphorylation of Smad1/5/8 in human hepatoma-derived cells and, synergistically with IL-6/STAT-3 signaling, up-regulates hepcidin expression. The effect on hepcidin is mediated through BMP signaling, most likely via activin receptor-like kinase 3 (ALK3). Inhbb mRNA is dramatically induced in mouse liver after LPS challenge, preceding Smad1/5/8 phosphorylation and hepcidin (Hamp) mRNA increases.\",\n      \"method\": \"In vivo LPS challenge, Smad1/5/8 phosphorylation assay, qPCR, ALK3 inhibitor treatment, primary hepatocyte assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vivo, cell-based, inhibitor), mechanistic pathway placement\",\n      \"pmids\": [\"22611157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Elevated activin B (among other activins) reduces skeletal muscle mass and function by stimulating the ActRIIB pathway, leading to increased transcription of atrophy-related ubiquitin ligases and decreased Akt/mTOR-mediated protein synthesis. Activin B was identified as one of the most potent negative regulators of muscle mass, and the resulting muscle wasting is fully reversible.\",\n      \"method\": \"rAAV6-mediated overexpression in mice, ActRIIB signaling assays, ubiquitin ligase expression assays, Akt/mTOR pathway analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with pathway analysis, multiple molecular readouts\",\n      \"pmids\": [\"24378873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNAi-mediated knockdown of INHBB in mouse granulosa cells arrests cells in G1 phase, increases apoptosis, and decreases estradiol and progesterone production. Mechanistically, INHBB knockdown downregulated Cyclin D1, Cyclin E, and Bcl2 protein expression while upregulating Bax, and reduced mRNA levels of CYP19A1 and CYP11A1, placing INHBB as a regulator of cell cycle progression and steroidogenesis in granulosa cells.\",\n      \"method\": \"RNAi knockdown, flow cytometry, Western blot, ELISA, qRT-PCR\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — loss-of-function with multiple molecular readouts, single lab\",\n      \"pmids\": [\"26063610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Menin represses Inhbb expression by facilitating recruitment of Ezh2 to the Inhbb promoter via an indirect mechanism involving Akt phosphorylation, resulting in H3K27me3 repressive marks at the Inhbb locus. Loss of Menin leads to reduced H3K27me3 at the Inhbb locus and increased activin B expression both in vitro and in vivo in insulinoma models.\",\n      \"method\": \"ChIP assay, H3K27me3 chromatin immunoprecipitation, Menin knockout cell lines and animal models, Akt inhibitor experiments\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and epigenetic assays with in vivo validation, single lab\",\n      \"pmids\": [\"28215965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sox9 directly binds to the INHBB enhancer and induces INHBB expression in hepatoma cells, promoting secretion of activin B. Secreted activin B in turn activates surrounding hepatic stellate cells through activin B/Smad signaling, promoting liver fibrosis and HCC metastasis. Inhibition of activin B/Smad signaling attenuated peri-tumoral fibrosis and metastasis.\",\n      \"method\": \"Gain- and loss-of-function experiments, ChIP assay (Sox9 binding to INHBB enhancer), orthotopic HCC tumor model, Smad signaling inhibition\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct Sox9-INHBB enhancer binding, in vivo validation, mechanistic pathway placement\",\n      \"pmids\": [\"33246092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tubular epithelial cell-derived INHBB (activin B) promotes renal fibrosis by activating surrounding interstitial fibroblasts in a paracrine manner through activin B/Smad signaling. Ectopic expression of INHBB in tubular cells initiates interstitial fibrosis in vivo, while INHBB inhibition blocks fibroblast activation and ameliorates fibrosis from ureteral obstruction or ischemia-reperfusion injury. Upregulation of INHBB in injured tubular cells depends on transcription factor Sox9.\",\n      \"method\": \"In vivo INHBB inhibition and ectopic overexpression in mouse fibrosis models, in vitro overexpression in tubular cells, Smad signaling assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain- and loss-of-function, paracrine mechanism with pathway placement, single lab\",\n      \"pmids\": [\"34543458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A missense variant in INHBB (p.Met360Thr/p.Met364Thr in mice) disrupts activin B biosynthesis in vitro without affecting inhibin B production, reducing circulating activin B levels. In knock-in mice, this variant increased testis size, Sertoli cell number, and round spermatid number without affecting fertility, demonstrating that activin B specifically regulates testis cell composition independent of FSH.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse model, in vitro biosynthesis assay, serum hormone analysis, histomorphometry\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR knock-in with in vitro biosynthesis validation, multiple phenotypic readouts\",\n      \"pmids\": [\"35022746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INHBB knockdown in human endometrial stromal cells suppresses ADCY1-mediated cAMP production and downstream cAMP signaling, thereby attenuating decidualization. RNA-seq identified INHBB-ADCY1 as a mechanistic axis, and a positive correlation between INHBB and ADCY1 expression was confirmed in endometria from recurrent implantation failure patients.\",\n      \"method\": \"siRNA knockdown, RNA-seq, cAMP analogue rescue experiment, qRT-PCR, Pearson correlation analysis\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — loss-of-function with pathway rescue, but pathway placement relies on correlation and single knockdown approach\",\n      \"pmids\": [\"36913138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"INHBB knockdown in colorectal cancer cells reduces migration, invasion, and hepatic metastasis in vivo by attenuating TGF-β/Smad2/3/Smad4 signaling (decreased Smad2/3 phosphorylation), reversing EMT (E-cadherin upregulation, N-cadherin and vimentin downregulation), and sensitizing cells to anoikis.\",\n      \"method\": \"siRNA knockdown in HCT116/Caco-2 cells, Western blot for Smad phosphorylation, EMT markers and anoikis assay, in vivo spleen injection xenograft model\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple molecular pathway readouts and in vivo validation\",\n      \"pmids\": [\"41380489\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INHBB encodes the inhibin βB subunit, which homodimerizes to form activin B (or heterodimerizes with βA to form activin AB) and signals through type II activin receptors (ActRIIA/IIB) and type I receptors ALK4 or ALK7 to activate Smad2/3 or, in hepatic contexts, Smad1/5/8 pathways; its transcription is controlled by Sox9 (via direct enhancer binding) and repressed by Menin through Akt/Ezh2-mediated H3K27me3 marks, while its biological roles include regulation of FSH secretion, skeletal muscle mass (via ActRIIB/atrogene pathway), hepcidin induction in inflammation (via ALK3/Smad1/5/8), granulosa cell cycle and steroidogenesis, renal and hepatic fibrosis (via paracrine Smad signaling to fibroblasts/stellate cells), endometrial decidualization (via ADCY1/cAMP), and testis cell composition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"INHBB encodes the inhibin βB subunit, which homodimerizes to form activin B — a secreted TGF-β superfamily ligand that signals through Smad2/3/Smad4 to regulate reproductive physiology, tissue fibrosis, and epithelial–mesenchymal transition. Activin B and activin A share overlapping receptor specificities; phenotypic differences between Inhba- and Inhbb-null mice arise primarily from spatiotemporal expression differences rather than distinct signaling mechanisms [PMID:10932194]. In granulosa cells, INHBB promotes cell cycle progression, survival, and steroidogenesis by sustaining Cyclin D1, Bcl2, and CYP19A1/CYP11A1 expression [PMID:26063610]; in endometrial stromal cells it drives decidualization through ADCY1/cAMP signaling [PMID:36913138]; and in epithelial–mesenchymal contexts, Sox9-induced INHBB expression enables paracrine activin B/Smad signaling that activates fibroblasts and promotes organ fibrosis [PMID:34543458, PMID:33246092]. INHBB transcription is epigenetically repressed by Menin through Akt-dependent Ezh2 recruitment and H3K27me3 deposition at the INHBB promoter [PMID:28215965], and specific INHBB coding variants that impair activin B assembly alter testis composition by increasing Sertoli cell and spermatid numbers [PMID:35022746].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The question of whether activin B has intrinsically distinct receptor specificity from activin A was resolved by showing that βB can functionally replace βA when expressed from the Inhba locus, establishing that expression pattern — not ligand identity — accounts for most phenotypic differences between subunit knockouts.\",\n      \"evidence\": \"Knock-in of Inhbb coding sequence into the Inhba locus in mice with phenotypic rescue analysis\",\n      \"pmids\": [\"10932194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether subtle receptor binding affinity differences exist between activin A and activin B that are context-dependent\",\n        \"Functional interchangeability was tested for craniofacial but not all Inhba-null phenotypes\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The cellular role of INHBB in the ovarian follicle was clarified by demonstrating that INHBB is required for granulosa cell proliferation, survival, and steroidogenic enzyme expression, linking the subunit directly to follicular function beyond FSH regulation.\",\n      \"evidence\": \"siRNA knockdown in primary mouse granulosa cells with flow cytometry, Western blot, and hormone ELISA\",\n      \"pmids\": [\"26063610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the observed effects reflect autocrine activin B signaling or another INHBB-containing dimer\",\n        \"In vivo granulosa-specific loss-of-function not performed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The mechanism controlling INHBB transcriptional repression was elucidated: Menin binds the INHBB promoter and recruits Ezh2 via Akt-dependent phosphorylation, depositing H3K27me3 to silence expression, explaining how loss of Menin leads to activin B upregulation.\",\n      \"evidence\": \"ChIP for Menin and H3K27me3 at the Inhbb locus in Menin-knockout mice and cell lines with Akt phosphorylation analysis\",\n      \"pmids\": [\"28215965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether other PcG components are required beyond Ezh2\",\n        \"Relevance of this epigenetic mechanism outside the endocrine pancreas context\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A paracrine pro-fibrotic mechanism was established in which Sox9 directly binds the INHBB enhancer in hepatocytes/hepatoma cells, inducing activin B secretion that activates hepatic stellate cells via Smad signaling to drive liver fibrosis and promote metastasis.\",\n      \"evidence\": \"ChIP-enhancer assay, gain/loss-of-function, orthotopic HCC mouse model with Smad pathway inhibition\",\n      \"pmids\": [\"33246092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the specific activin receptor(s) on stellate cells mediating this paracrine signal\",\n        \"Whether inhibin B (αβB) counteracts this pathway in the same tissue context\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The Sox9–INHBB–activin B paracrine fibrosis axis was generalized to the kidney, where TEC-derived activin B activates interstitial fibroblasts via Smad signaling; in vivo INHBB inhibition blocked fibrosis while TEC-specific overexpression was sufficient to initiate it.\",\n      \"evidence\": \"UUO and ischemia–reperfusion mouse models with INHBB overexpression/inhibition and fibroblast co-culture\",\n      \"pmids\": [\"34543458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether endogenous inhibin α subunit expression modulates the fibrotic activin B signal in kidney\",\n        \"The precise Sox9-binding element in the INHBB enhancer in renal cells versus hepatocytes\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The structural requirements for activin B assembly were addressed by showing that a human INHBB missense variant (p.Met360Thr) disrupts activin B biosynthesis and secretion, leading to reduced circulating activin B and altered testis composition with expanded Sertoli cells and spermatids.\",\n      \"evidence\": \"CRISPR/Cas9 knock-in mouse; serum hormone analysis; in vitro biosynthesis assay; testis histomorphometry\",\n      \"pmids\": [\"35022746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether fertility is functionally impaired in these mice\",\n        \"No crystal structure to explain how M360T disrupts dimerization\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"INHBB was placed upstream of the ADCY1/cAMP axis in endometrial decidualization, showing that INHBB knockdown reduces ADCY1 expression and cAMP levels in stromal cells, thereby impairing the decidualization program.\",\n      \"evidence\": \"siRNA knockdown in human endometrial stromal cells with RNA-seq, RT-qPCR, and cAMP signaling readouts\",\n      \"pmids\": [\"36913138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether activin B acts through canonical Smad or non-canonical signaling to induce ADCY1\",\n        \"No rescue experiment with exogenous activin B or cAMP analog\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The pro-metastatic role of INHBB-driven Smad signaling was extended to colorectal cancer, where INHBB knockdown reduces Smad2/3 phosphorylation, reverses EMT, and sensitizes cells to anoikis, decreasing hepatic metastasis in vivo.\",\n      \"evidence\": \"siRNA knockdown in CRC cell lines; Western blot for p-Smad2/3 and EMT markers; xenograft spleen-injection metastasis model\",\n      \"pmids\": [\"41380489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the effect is mediated by activin B homodimer versus activin AB heterodimer\",\n        \"Contribution of autocrine versus paracrine activin B signaling in CRC not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for activin B dimerization and receptor engagement, the full spectrum of activin B versus inhibin B functions in vivo, and how the Sox9–INHBB–Smad fibrosis axis is regulated in different organ contexts remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of activin B in complex with its type I/II receptors\",\n        \"In vivo conditional INHBB knockout studies in adult tissues beyond gonads are lacking\",\n        \"Cross-regulation between inhibin B and activin B in paracrine fibrosis signaling not addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3, 4, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 4, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\n      \"Activin B homodimer (βB-βB)\",\n      \"Inhibin B heterodimer (α-βB)\"\n    ],\n    \"partners\": [\n      \"INHBA\",\n      \"INHA\",\n      \"SOX9\",\n      \"MEN1\",\n      \"EZH2\",\n      \"SMAD2\",\n      \"SMAD3\",\n      \"SMAD4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"INHBB encodes the inhibin βB subunit, which homodimerizes to form activin B or heterodimerizes with βA to form activin AB; these TGF-β superfamily ligands signal through type II activin receptors (ActRIIA/ActRIIB) and type I receptors ALK4/ALK7 to activate Smad2/3, or, in hepatic contexts, ALK3 to activate Smad1/5/8 [PMID:2575216, PMID:15196700, PMID:22611157]. Activin B circulates as an endocrine factor and acts as a potent regulator of FSH secretion, skeletal muscle mass (via ActRIIB/atrogene induction), inflammation-induced hepcidin expression, and testis cell composition [PMID:18927237, PMID:24378873, PMID:22611157, PMID:35022746]. In paracrine settings, INHBB-derived activin B produced by injured epithelial cells activates fibroblasts and stellate cells through Smad signaling to promote renal and hepatic fibrosis, and drives EMT and metastasis in colorectal and hepatocellular carcinoma models [PMID:34543458, PMID:33246092, PMID:41380489]. Transcription of INHBB is positively regulated by Sox9 via direct enhancer binding and repressed by Menin through Akt/Ezh2-mediated H3K27me3 deposition [PMID:33246092, PMID:28215965].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Identification of INHBB as a distinct inhibin β subunit gene established that inhibin exists in two forms (βA and βB) sharing a common alpha chain, laying the molecular foundation for understanding activin/inhibin diversity.\",\n      \"evidence\": \"cDNA cloning and sequencing of the human βB subunit from ovarian cDNA libraries\",\n      \"pmids\": [\"3754442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional assay for the βB subunit alone\", \"Dimerization partners and receptor not yet identified\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Reconstitution of activin B from cloned INHBB cDNA demonstrated that the βB subunit homodimerizes to form a bioactive ligand indistinguishable from activin A in stimulating FSH release and erythroid differentiation, establishing activin B as a functional TGF-β superfamily member.\",\n      \"evidence\": \"Transfection/secretion in mammalian cells, pituitary FSH bioassay, K562 hemoglobin induction assay\",\n      \"pmids\": [\"2575216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity unknown\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Demonstration that activin B binds a cloned transmembrane serine/threonine kinase receptor with subnanomolar affinity and competes with activin A resolved how both activin isoforms converge on a shared receptor system.\",\n      \"evidence\": \"Radioligand binding and competition assay in COS cells expressing cloned activin receptor\",\n      \"pmids\": [\"1646080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Type I receptor specificity not defined\", \"Intracellular signaling cascade downstream of binding unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"A knock-in replacing Inhba coding sequence with Inhbb showed that activin B can rescue activin A-dependent craniofacial development but cannot fully substitute in testicular, genital, and hair phenotypes, establishing both overlapping and distinct biological activities for the two activin isoforms in vivo.\",\n      \"evidence\": \"Gene targeting knock-in in mice, systematic phenotypic analysis\",\n      \"pmids\": [\"10932194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of differential bioactivity not resolved\", \"Whether differences reflect receptor affinity or tissue availability unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of ALK7 as a preferential type I receptor for activin B (versus ALK4 for activin A) and demonstration that activin B stimulates insulin secretion through ALK7/ActRIIA provided a mechanistic basis for isoform-specific signaling.\",\n      \"evidence\": \"Receptor binding assays, reporter gene assays, and insulin secretion assays in MIN6 pancreatic β-cells\",\n      \"pmids\": [\"15196700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for ALK7 selectivity not determined\", \"In vivo relevance of ALK7-mediated insulin secretion not confirmed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Affinity-purification of activin B from native human and mouse serum confirmed its status as a circulating endocrine factor and revealed that it, like myostatin, inhibits myoblast differentiation, expanding its role beyond reproductive endocrinology to muscle biology.\",\n      \"evidence\": \"Soluble ActRII/ActRIIB affinity purification from serum, mass spectrometry, myoblast differentiation assay\",\n      \"pmids\": [\"18927237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo muscle mass effects not yet demonstrated\", \"Relative contribution versus myostatin unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Activin B was shown to induce hepcidin via Smad1/5/8 phosphorylation through ALK3 in hepatocytes, synergizing with IL-6/STAT3, establishing a non-canonical BMP-like signaling mode for activin B in inflammatory iron regulation.\",\n      \"evidence\": \"LPS challenge in mice, Smad1/5/8 phosphorylation assays, ALK3 inhibitor studies, primary hepatocyte assays\",\n      \"pmids\": [\"22611157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ALK3 engagement is direct or requires co-receptors not resolved\", \"Contribution relative to BMP6 in hepcidin induction in vivo unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"In vivo overexpression of activin B in muscle demonstrated that it is a potent inducer of atrophy through ActRIIB-mediated upregulation of atrogenes and suppression of Akt/mTOR protein synthesis, confirming a direct catabolic role in skeletal muscle.\",\n      \"evidence\": \"rAAV6-mediated overexpression in mouse muscle, ubiquitin ligase and Akt/mTOR pathway analysis\",\n      \"pmids\": [\"24378873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous activin B contribution to cachexia not proven by loss-of-function\", \"Relative potency versus activin A in muscle wasting not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Epigenetic regulation of INHBB transcription was resolved: Menin recruits Ezh2 via Akt-dependent phosphorylation to deposit H3K27me3 repressive marks at the Inhbb locus, and Menin loss de-represses activin B in insulinoma, linking tumor suppressor pathways to activin B expression.\",\n      \"evidence\": \"ChIP for H3K27me3 and Ezh2, Menin-knockout cell lines, Akt inhibitor experiments, in vivo insulinoma models\",\n      \"pmids\": [\"28215965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Menin-Ezh2 regulation of INHBB operates outside pancreatic neuroendocrine tissue not established\", \"Direct versus indirect Akt-Ezh2 link not fully dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Sox9 was identified as a direct transcriptional activator of INHBB via enhancer binding, and secreted activin B was shown to activate hepatic stellate cells through Smad signaling to promote fibrosis and metastasis, establishing a Sox9-INHBB-Smad paracrine axis in the liver tumor microenvironment.\",\n      \"evidence\": \"ChIP for Sox9 at INHBB enhancer, orthotopic HCC model, Smad signaling inhibition\",\n      \"pmids\": [\"33246092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Sox9 regulation of INHBB is tissue-general or liver-specific not determined\", \"Identity of specific Smad pathway (Smad2/3 vs Smad1/5/8) in stellate cell activation not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extension of the paracrine fibrosis paradigm to kidney showed that tubular epithelial INHBB activates interstitial fibroblasts through activin B/Smad signaling, with INHBB inhibition ameliorating renal fibrosis, generalizing the injured-epithelium-to-fibroblast paracrine mechanism.\",\n      \"evidence\": \"In vivo INHBB overexpression and inhibition in UUO and ischemia-reperfusion injury mouse models, Smad signaling assays\",\n      \"pmids\": [\"34543458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific Smad isoform usage in renal fibroblasts not determined\", \"Whether follistatin or other endogenous antagonists modulate this axis in vivo not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A missense INHBB variant that selectively disrupts activin B (but not inhibin B) biosynthesis increased Sertoli and spermatid cell numbers in knock-in mice without affecting fertility, disentangling activin B from inhibin B function and demonstrating a specific role for activin B in testis cell composition.\",\n      \"evidence\": \"CRISPR/Cas9 knock-in mice, in vitro biosynthesis assay, serum hormone analysis, histomorphometry\",\n      \"pmids\": [\"35022746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which reduced activin B increases Sertoli cell number not identified\", \"Whether this variant affects activin AB heterodimerization not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"INHBB was linked to endometrial decidualization through an ADCY1/cAMP axis, where INHBB knockdown suppressed cAMP production and downstream decidualization markers, connecting activin B to non-Smad signaling in reproductive biology.\",\n      \"evidence\": \"siRNA knockdown in human endometrial stromal cells, RNA-seq, cAMP analogue rescue\",\n      \"pmids\": [\"36913138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether activin B directly upregulates ADCY1 transcription or acts indirectly not resolved\", \"Receptor and Smad-independence of this pathway not formally tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"INHBB was shown to promote colorectal cancer metastasis by sustaining Smad2/3/Smad4 phosphorylation, EMT, and anoikis resistance, extending the pro-metastatic role of activin B signaling beyond HCC to additional gastrointestinal cancers.\",\n      \"evidence\": \"siRNA knockdown in CRC cell lines, Smad phosphorylation and EMT marker analysis, splenic injection xenograft hepatic metastasis model\",\n      \"pmids\": [\"41380489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect is autocrine or paracrine in the metastatic niche not distinguished\", \"Activin B-specific versus pan-activin contribution not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for activin B's selective engagement of ALK7 versus ALK4, the relative in vivo contribution of activin B versus other ActRIIB ligands (myostatin, GDF11) in muscle wasting, and the mechanism linking activin B to ADCY1/cAMP signaling independently of canonical Smad pathways remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of activin B in complex with ALK7\", \"No conditional Inhbb knockout dissecting endogenous activin B roles across tissues\", \"Smad-independent signaling mechanisms of activin B poorly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 5, 6, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 6, 7, 11, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 7, 8, 11, 12, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [9, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 12, 15]}\n    ],\n    \"complexes\": [\n      \"Activin B homodimer (βB-βB)\",\n      \"Activin AB heterodimer (βA-βB)\",\n      \"Inhibin B heterodimer (α-βB)\"\n    ],\n    \"partners\": [\n      \"INHBA\",\n      \"INHA\",\n      \"ACVR2A\",\n      \"ACVR2B\",\n      \"ACVR1C\",\n      \"ACVR1B\",\n      \"SOX9\",\n      \"MEN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}