INHBB

INHBB encodes the inhibin βB subunit, the building block of activin B, a secreted TGF-β-family ligand that signals through Smad pathways to control reproductive tissue homeostasis and to drive paracrine fibrosis and tumor progression (PMID:10932194, PMID:33246092). The βB subunit is functionally interchangeable with the βA subunit (activin A) when expressed from the same locus, yet confers distinct dosage-dependent bioactivities affecting somatic, testicular, genital, and hair phenotypes (PMID:10932194); a conserved residue (Met360/Met364) is specifically required for activin B biosynthesis and secretion without affecting inhibin B production, and its disruption enlarges testes with increased Sertoli cell and spermatid numbers (PMID:35022746). In the ovary, INHBB sustains granulosa cell cycle progression and survival and supports estradiol/progesterone synthesis via CYP19A1 and CYP11A1 (PMID:26063610), while in the endometrium it promotes decidualization through an INHBB–ADCY1–cAMP axis (PMID:36913138). INHBB transcription is activated by direct Sox9 enhancer binding (PMID:33246092) and repressed by Menin, which recruits Ezh2 to deposit H3K27me3 at the locus through an Akt-dependent mechanism (PMID:28215965). In disease, Sox9-driven INHBB induction in hepatoma and tubular epithelial cells secretes activin B that activates hepatic stellate cells and interstitial fibroblasts through activin B/Smad signaling, driving liver and renal fibrosis and metastasis (PMID:33246092, PMID:34543458); in colorectal cancer cells INHBB promotes migration, invasion, EMT, and anoikis resistance via TGF-β/Smad2/3/Smad4 signaling (PMID:41380489).

1. 2000 High

   Established whether the βB and βA subunits encode functionally equivalent ligands, resolving whether activin B has activities distinct from activin A.

   Evidence Genetic knock-in of Inhbb coding sequence into the Inhba locus with phenotypic rescue analysis in mice

   PMID:10932194

   Open questions at the time

   • Did not define the molecular signaling differences underlying the distinct activin B phenotypes
   • Interchangeability tested only from the Inhba locus, not at endogenous expression contexts
2. 2015 Medium

   Defined the cell-autonomous role of INHBB in the ovary, linking it to granulosa cell cycle progression, survival, and steroidogenesis.

   Evidence shRNA knockdown in mouse granulosa cells with flow cytometry, ELISA, Western blot, and qRT-PCR

   PMID:26063610

   Open questions at the time

   • Did not establish whether effects are mediated by activin B autocrine signaling or by inhibin B
   • Signaling pathway downstream of INHBB not mapped
3. 2017 Medium

   Identified an epigenetic mechanism controlling INHBB transcription, showing Menin represses the locus to limit activin B output.

   Evidence Men1 KO mice and cell lines with ChIP for Menin promoter binding, H3K27me3 analysis, and pharmacological Akt modulation

   PMID:28215965

   Open questions at the time

   • Ezh2 recruitment shown to be indirect but the bridging factor not identified
   • Physiological contexts where this repression operates not fully defined
4. 2020 Medium

   Demonstrated transcriptional activation of INHBB by Sox9 and established activin B as a paracrine driver of hepatic stellate cell activation in liver fibrosis and HCC metastasis.

   Evidence Sox9 enhancer binding assays, gain/loss-of-function, activin B/Smad inhibition, and orthotopic HCC mouse model

   PMID:33246092

   Open questions at the time

   • Direct receptor engagement on stellate cells not characterized
   • Single-lab study
5. 2021 Medium

   Generalized the Sox9–INHBB–activin B/Smad paracrine fibrotic axis to the kidney, showing tubular epithelial INHBB activates interstitial fibroblasts.

   Evidence UUO and IRI mouse models, ectopic INHBB overexpression in TECs, Smad inhibition, histology and fibrosis markers

   PMID:34543458

   Open questions at the time

   • Receptor and downstream effectors in fibroblasts not defined
   • Single-lab study
6. 2022 High

   Resolved which structural determinant separates activin B from inhibin B biosynthesis and linked an INHBB variant to testicular phenotypes.

   Evidence CRISPR/Cas9 knock-in mouse modeling a human missense variant, serum hormone assays, testis histomorphometry, and in vitro biosynthesis assays for two variants

   PMID:35022746

   Open questions at the time

   • Mechanism by which the residue selectively impairs activin B but not inhibin B assembly not structurally resolved
   • Human clinical consequences of the variants not established
7. 2023 Medium

   Defined INHBB function in human endometrium, identifying the INHBB–ADCY1–cAMP axis as required for decidualization.

   Evidence siRNA knockdown in HESCs, RNA-seq, forskolin rescue, immunofluorescence, and correlation analysis in RIF patient endometria

   PMID:36913138

   Open questions at the time

   • How INHBB connects to ADCY1 transcriptionally not mechanistically resolved
   • Correlative human data not causal
8. 2025 Medium

   Extended the pro-metastatic role of INHBB to colorectal cancer via TGF-β/Smad-driven EMT and anoikis resistance.

   Evidence siRNA knockdown in HCT116/Caco-2, transwell and anoikis assays, Western blot for Smad phosphorylation and EMT markers, and xenograft spleen-injection metastasis model

   PMID:41380489

   Open questions at the time

   • Whether effect is autocrine activin B signaling versus intracellular role not distinguished
   • Receptor complex engaged not identified

• The activin B receptor complexes and the structural basis for βB dimerization choice (activin B versus inhibin B) across the diverse reproductive, fibrotic, and oncogenic contexts remain unresolved.
• No receptor identified for activin B in any of the characterized tissues
• No structural model of the βB dimerization interface
• Tissue-specific determinants of dimer partner choice unknown