{"gene":"INHBE","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2022,"finding":"Heterozygous protein-truncating mutations in INHBE (encoding the hepatokine activin E) associate with favorable fat distribution (lower waist-to-hip ratio) and ~28% lower odds of type 2 diabetes; the most common pLOF variant causes an in-frame deletion resulting in 90% reduction in secreted activin E protein, establishing INHBE as a liver-expressed negative regulator of adipose storage.","method":"Exome sequencing in 618,375 individuals combined with in vitro characterization of pLOF variant showing reduced secreted protein levels","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — large-scale human genetics (exome-wide) replicated across multiple cohorts plus in vitro functional characterization of protein secretion","pmids":["35999217"],"is_preprint":false},{"year":2022,"finding":"Predicted loss-of-function variants in INHBE associate with lower waist-to-hip ratio adjusted for BMI; additionally, variants in ACVR1C (encoding an activin receptor) show the same association, further indicating that the activin E–ACVR1C signaling axis regulates abdominal fat distribution.","method":"Exome sequencing in 362,679 individuals with replication in AMP-T2D-GENES; in vitro characterization of the most common pLOF variant showing 90% reduction in secreted protein","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — replicated across independent cohorts with functional validation of reduced protein secretion","pmids":["35896531"],"is_preprint":false},{"year":2003,"finding":"Overexpression of activin βE (the INHBE-encoded subunit) in mouse liver via nonviral gene transfer temporarily inhibited regenerative DNA synthesis in hepatocytes and non-parenchymal cells, demonstrating that activin E has a growth-inhibitory biological activity in liver tissue homeostasis.","method":"In vivo nonviral hydrodynamic gene transfer to mouse liver, mRNA analysis, reporter gene co-expression, measurement of DNA synthesis during liver regeneration","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vivo loss-of-function/gain-of-function with quantitative DNA synthesis readout, single lab","pmids":["12865331"],"is_preprint":false},{"year":2006,"finding":"Activin βE (INHBE product) is expressed in hepatocytes and is downregulated in rat and human liver tumors; follistatin administration stimulated DNA synthesis preferentially in preneoplastic hepatocytes while activin A repressed it, consistent with activin E functioning as part of a growth-suppressive activin/follistatin balance in the liver.","method":"Real-time PCR, immunohistochemistry in chemically induced rat and human liver tumors; DNA synthesis assays with follistatin and activin A treatment","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 3 — expression and functional data from the same lab, single study; functional read-out used activin A as proxy for the activin/follistatin axis","pmids":["16935389"],"is_preprint":false}],"current_model":"INHBE encodes activin E (inhibin βE), a hepatocyte-secreted member of the activin family that acts as a circulating negative regulator of adipose fat storage; human loss-of-function mutations that reduce secreted activin E levels are associated with favorable fat distribution and protection from type 2 diabetes, while liver-directed overexpression studies in mice show that activin E inhibits hepatocyte DNA synthesis, implicating it in liver growth homeostasis."},"narrative":{"teleology":[{"year":2003,"claim":"Whether activin βE has any biological activity was unknown; liver-directed overexpression demonstrated that it inhibits hepatocyte DNA synthesis during regeneration, establishing activin E as a growth-inhibitory factor in the liver.","evidence":"In vivo nonviral hydrodynamic gene transfer to mouse liver with measurement of DNA synthesis during liver regeneration","pmids":["12865331"],"confidence":"Medium","gaps":["Single gain-of-function approach without genetic loss-of-function confirmation in vivo","Whether endogenous activin E levels are sufficient to regulate liver regeneration was not tested","Receptor and downstream signaling pathway mediating the growth-inhibitory effect were not identified"]},{"year":2006,"claim":"The relevance of activin βE to liver pathology was unclear; demonstration that INHBE is expressed in hepatocytes and downregulated in liver tumors positioned activin E within the growth-suppressive activin/follistatin axis in hepatocarcinogenesis.","evidence":"Real-time PCR and immunohistochemistry in chemically induced rat liver tumors and human liver tumors; DNA synthesis assays with follistatin and activin A","pmids":["16935389"],"confidence":"Medium","gaps":["Growth-suppressive effects were demonstrated with activin A, not activin E directly, so the specific contribution of activin E to tumor suppression remains inferred","No genetic manipulation of INHBE in tumor models","Mechanism of INHBE downregulation in tumors was not elucidated"]},{"year":2022,"claim":"Whether activin E has systemic metabolic functions was unknown; large-scale human exome studies revealed that INHBE loss-of-function variants confer favorable fat distribution and protection from type 2 diabetes, and concordant findings in the receptor gene ACVR1C established an activin E–ACVR1C signaling axis governing abdominal adiposity.","evidence":"Exome sequencing in >600,000 individuals across multiple cohorts with replication; in vitro characterization showing ~90% reduction in secreted protein for the most common pLOF variant","pmids":["35999217","35896531"],"confidence":"High","gaps":["Direct demonstration of activin E signaling through ACVR1C at the biochemical level has not been shown","Mechanism by which reduced circulating activin E alters adipose tissue biology is unknown","No animal loss-of-function model has confirmed the metabolic phenotype"]},{"year":null,"claim":"Key open questions include the precise receptor complex engaged by activin E homodimers or heterodimers, the intracellular signaling cascade (Smad versus non-Smad) in adipocytes, and whether the liver growth-suppressive and metabolic roles are mediated through the same or distinct pathways.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure or binding affinity data for activin E with type I/II receptors","No conditional knockout or knockdown model in liver or adipose tissue","Whether activin E acts as homodimer or heterodimer with other β subunits in vivo is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["ACVR1C"],"other_free_text":[]},"mechanistic_narrative":"INHBE encodes activin βE, a liver-expressed secreted member of the TGF-β/activin family that functions as a hepatokine regulating both adipose fat storage and hepatocyte proliferation. In human genetics studies, heterozygous protein-truncating variants in INHBE—which reduce secreted activin E protein by ~90%—associate with favorable fat distribution (lower waist-to-hip ratio) and ~28% reduced odds of type 2 diabetes, and convergent loss-of-function associations in the receptor gene ACVR1C confirm that the activin E–ACVR1C signaling axis governs abdominal adiposity [PMID:35999217, PMID:35896531]. Overexpression of activin βE in mouse liver inhibits regenerative DNA synthesis in hepatocytes, and activin βE is downregulated in rat and human liver tumors, indicating an additional growth-suppressive role in liver tissue homeostasis [PMID:12865331, PMID:16935389]."},"prefetch_data":{"uniprot":{"accession":"P58166","full_name":"Inhibin beta E chain","aliases":["Activin beta-E chain"],"length_aa":350,"mass_kda":38.6,"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 E is a homodimer of INHBE secreted by the liver that plays a crucial role in regulating metabolic homeostasis particularly in lipid metabolism and energy homeostasis. Plays a central role in the regulation of adipose tissue lipolysis by preventing the influx of fatty acids from adipose tissue into the liver. Mechanistically, signals via ACVR1C to activate SMAD2/3 signaling, suppressing PPARG target genes in adipose tissue, thereby reducing liver lipid content and improving glycemic control (PubMed:38533769). Induces beige adipocyte formation and thermogenesis in response to cold exposure (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P58166/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INHBE","classification":"Not Classified","n_dependent_lines":160,"n_total_lines":1208,"dependency_fraction":0.13245033112582782},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/INHBE","total_profiled":1310},"omim":[{"mim_id":"612031","title":"INHIBIN, BETA E; INHBE","url":"https://www.omim.org/entry/612031"},{"mim_id":"192977","title":"VERY LOW DENSITY LIPOPROTEIN RECEPTOR; VLDLR","url":"https://www.omim.org/entry/192977"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":134.1}],"url":"https://www.proteinatlas.org/search/INHBE"},"hgnc":{"alias_symbol":["activin","MGC4638"],"prev_symbol":[]},"alphafold":{"accession":"P58166","domains":[{"cath_id":"2.10.90.10","chopping":"37-79_237-350","consensus_level":"high","plddt":82.7062,"start":37,"end":350},{"cath_id":"2.60.120.970","chopping":"90-196_207-226","consensus_level":"high","plddt":78.1651,"start":90,"end":226}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P58166","model_url":"https://alphafold.ebi.ac.uk/files/AF-P58166-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P58166-F1-predicted_aligned_error_v6.png","plddt_mean":74.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INHBE","jax_strain_url":"https://www.jax.org/strain/search?query=INHBE"},"sequence":{"accession":"P58166","fasta_url":"https://rest.uniprot.org/uniprotkb/P58166.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P58166/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P58166"}},"corpus_meta":[{"pmid":"9288972","id":"PMC_9288972","title":"Smad4 and FAST-1 in the assembly of activin-responsive factor.","date":"1997","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9288972","citation_count":496,"is_preprint":false},{"pmid":"7885474","id":"PMC_7885474","title":"Different phenotypes for mice deficient in either activins or activin receptor type II.","date":"1995","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/7885474","citation_count":476,"is_preprint":false},{"pmid":"8168134","id":"PMC_8168134","title":"Inhibition of activin receptor signaling promotes neuralization in Xenopus.","date":"1994","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8168134","citation_count":408,"is_preprint":false},{"pmid":"26333933","id":"PMC_26333933","title":"ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.","date":"2015","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26333933","citation_count":357,"is_preprint":false},{"pmid":"19279133","id":"PMC_19279133","title":"Activin/Nodal signalling maintains pluripotency by controlling Nanog expression.","date":"2009","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19279133","citation_count":336,"is_preprint":false},{"pmid":"8622651","id":"PMC_8622651","title":"Activation of signalling by the activin receptor complex.","date":"1996","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8622651","citation_count":296,"is_preprint":false},{"pmid":"2036994","id":"PMC_2036994","title":"Follistatin binds to both activin and inhibin through the common subunit.","date":"1991","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/2036994","citation_count":270,"is_preprint":false},{"pmid":"23721881","id":"PMC_23721881","title":"Myostatin/activin pathway antagonism: molecular basis and therapeutic potential.","date":"2013","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23721881","citation_count":251,"is_preprint":false},{"pmid":"8149921","id":"PMC_8149921","title":"Mesoderm induction by activin requires FGF-mediated intracellular signals.","date":"1994","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8149921","citation_count":216,"is_preprint":false},{"pmid":"19273500","id":"PMC_19273500","title":"The biology of activin: recent advances in structure, regulation and function.","date":"2009","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19273500","citation_count":200,"is_preprint":false},{"pmid":"11815670","id":"PMC_11815670","title":"Regulation of cell proliferation, apoptosis, and carcinogenesis by activin.","date":"2002","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/11815670","citation_count":188,"is_preprint":false},{"pmid":"16481210","id":"PMC_16481210","title":"Roles of activin in tissue repair, fibrosis, and inflammatory disease.","date":"2006","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/16481210","citation_count":187,"is_preprint":false},{"pmid":"15734148","id":"PMC_15734148","title":"Antagonists of activin signaling: mechanisms and potential biological applications.","date":"2005","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/15734148","citation_count":174,"is_preprint":false},{"pmid":"8606007","id":"PMC_8606007","title":"Strong induction of activin expression after injury suggests an important role of activin in wound repair.","date":"1996","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/8606007","citation_count":163,"is_preprint":false},{"pmid":"30540228","id":"PMC_30540228","title":"Activin A in Mammalian Physiology.","date":"2019","source":"Physiological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/30540228","citation_count":149,"is_preprint":false},{"pmid":"8226823","id":"PMC_8226823","title":"Inhibition of vascular endothelial cell growth by activin-A.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8226823","citation_count":134,"is_preprint":false},{"pmid":"26047946","id":"PMC_26047946","title":"Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B.","date":"2015","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/26047946","citation_count":129,"is_preprint":false},{"pmid":"9605419","id":"PMC_9605419","title":"Regulation of cellular and system function by activin.","date":"1998","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/9605419","citation_count":126,"is_preprint":false},{"pmid":"8732684","id":"PMC_8732684","title":"Activin signaling through activin receptor type II causes the cachexia-like symptoms in inhibin-deficient mice.","date":"1996","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/8732684","citation_count":124,"is_preprint":false},{"pmid":"9733712","id":"PMC_9733712","title":"Smad7 is an activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9733712","citation_count":110,"is_preprint":false},{"pmid":"15319828","id":"PMC_15319828","title":"Regulation of gonadotropins by inhibin and activin.","date":"2004","source":"Seminars in reproductive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15319828","citation_count":108,"is_preprint":false},{"pmid":"8415726","id":"PMC_8415726","title":"Identification of a Drosophila activin receptor.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8415726","citation_count":105,"is_preprint":false},{"pmid":"7589799","id":"PMC_7589799","title":"Activin and its receptors during gastrulation and the later phases of mesoderm development in the chick embryo.","date":"1995","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/7589799","citation_count":103,"is_preprint":false},{"pmid":"8721982","id":"PMC_8721982","title":"Formation and activation by phosphorylation of activin receptor complexes.","date":"1996","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/8721982","citation_count":101,"is_preprint":false},{"pmid":"11738794","id":"PMC_11738794","title":"Intra-follicular activin availability is altered in prenatally-androgenized lambs.","date":"2001","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11738794","citation_count":95,"is_preprint":false},{"pmid":"24333131","id":"PMC_24333131","title":"A myostatin and activin decoy receptor enhances bone formation in mice.","date":"2013","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/24333131","citation_count":91,"is_preprint":false},{"pmid":"11511564","id":"PMC_11511564","title":"Overexpression of activin A in stage IV colorectal cancer.","date":"2001","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/11511564","citation_count":88,"is_preprint":false},{"pmid":"3216863","id":"PMC_3216863","title":"Recombinant expression and characterization of human activin A.","date":"1988","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/3216863","citation_count":86,"is_preprint":false},{"pmid":"16997617","id":"PMC_16997617","title":"The activin axis in liver biology and disease.","date":"2006","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/16997617","citation_count":86,"is_preprint":false},{"pmid":"11427154","id":"PMC_11427154","title":"Roles of activin and its signal transduction mechanisms in reproductive tissues.","date":"2001","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11427154","citation_count":86,"is_preprint":false},{"pmid":"27373274","id":"PMC_27373274","title":"Structure and activation of pro-activin A.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27373274","citation_count":82,"is_preprint":false},{"pmid":"21763751","id":"PMC_21763751","title":"New insights into the mechanisms of activin action and inhibition.","date":"2011","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21763751","citation_count":80,"is_preprint":false},{"pmid":"1426642","id":"PMC_1426642","title":"Interaction of Wnt and activin in dorsal mesoderm induction in Xenopus.","date":"1992","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/1426642","citation_count":80,"is_preprint":false},{"pmid":"11451566","id":"PMC_11451566","title":"The transcriptional role of Smads and FAST (FoxH1) in TGFbeta and activin signalling.","date":"2001","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11451566","citation_count":78,"is_preprint":false},{"pmid":"9034128","id":"PMC_9034128","title":"Activins and activin receptors in cell growth.","date":"1997","source":"Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9034128","citation_count":78,"is_preprint":false},{"pmid":"9496947","id":"PMC_9496947","title":"Expression of activin A is increased in cirrhotic and fibrotic rat livers.","date":"1998","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/9496947","citation_count":78,"is_preprint":false},{"pmid":"11451583","id":"PMC_11451583","title":"Production and actions of inhibin and activin during folliculogenesis in the rat.","date":"2001","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11451583","citation_count":74,"is_preprint":false},{"pmid":"15451577","id":"PMC_15451577","title":"Activin: an important regulator of wound repair, fibrosis, and neuroprotection.","date":"2004","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15451577","citation_count":74,"is_preprint":false},{"pmid":"12865331","id":"PMC_12865331","title":"Overexpression of activin beta(C) or activin beta(E) in the mouse liver inhibits regenerative deoxyribonucleic acid synthesis of hepatic cells.","date":"2003","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/12865331","citation_count":73,"is_preprint":false},{"pmid":"12606325","id":"PMC_12606325","title":"Activin signaling pathways in ovine pituitary and LbetaT2 gonadotrope cells.","date":"2002","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/12606325","citation_count":71,"is_preprint":false},{"pmid":"9360531","id":"PMC_9360531","title":"Presence of activin, inhibin, and follistatin in epithelial ovarian carcinoma.","date":"1997","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/9360531","citation_count":71,"is_preprint":false},{"pmid":"7588300","id":"PMC_7588300","title":"Inactivation of activin-dependent transcription by kinase-deficient activin receptors.","date":"1995","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/7588300","citation_count":68,"is_preprint":false},{"pmid":"9570994","id":"PMC_9570994","title":"Imbalanced expression of inhibin and activin subunits in primary epithelial ovarian cancer.","date":"1998","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/9570994","citation_count":67,"is_preprint":false},{"pmid":"7705698","id":"PMC_7705698","title":"Inhibin and activin are demonstrable by immunohistochemistry in ovarian tumor tissue.","date":"1995","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/7705698","citation_count":66,"is_preprint":false},{"pmid":"15753386","id":"PMC_15753386","title":"Activin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanisms.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15753386","citation_count":66,"is_preprint":false},{"pmid":"18171686","id":"PMC_18171686","title":"Drosophila Activin- and the Activin-like product Dawdle function redundantly to regulate proliferation in the larval brain.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18171686","citation_count":64,"is_preprint":false},{"pmid":"8774270","id":"PMC_8774270","title":"Inhibin, activin, and follistatin in reproductive medicine.","date":"1996","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/8774270","citation_count":62,"is_preprint":false},{"pmid":"17040568","id":"PMC_17040568","title":"Activin B can signal through both ALK4 and ALK7 in gonadotrope cells.","date":"2006","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/17040568","citation_count":62,"is_preprint":false},{"pmid":"12456957","id":"PMC_12456957","title":"The role of activin a in regulation of hemopoiesis.","date":"2002","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/12456957","citation_count":61,"is_preprint":false},{"pmid":"11956142","id":"PMC_11956142","title":"Follistatin-related protein and follistatin differentially neutralize endogenous vs. exogenous activin.","date":"2002","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11956142","citation_count":61,"is_preprint":false},{"pmid":"15451568","id":"PMC_15451568","title":"The role of activin, follistatin and inhibin in testicular physiology.","date":"2004","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15451568","citation_count":59,"is_preprint":false},{"pmid":"15253386","id":"PMC_15253386","title":"Activin receptor signaling.","date":"2004","source":"Growth factors (Chur, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/15253386","citation_count":58,"is_preprint":false},{"pmid":"18350601","id":"PMC_18350601","title":"Activins and activin antagonists in hepatocellular carcinoma.","date":"2008","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/18350601","citation_count":58,"is_preprint":false},{"pmid":"29397421","id":"PMC_29397421","title":"Activin receptors regulate the oligodendrocyte lineage in health and disease.","date":"2018","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/29397421","citation_count":57,"is_preprint":false},{"pmid":"18089557","id":"PMC_18089557","title":"Cripto is a noncompetitive activin antagonist that forms analogous signaling complexes with activin and nodal.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18089557","citation_count":57,"is_preprint":false},{"pmid":"11572790","id":"PMC_11572790","title":"Activin A and activin receptors in gestational tissue from preeclamptic pregnancies.","date":"2001","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11572790","citation_count":56,"is_preprint":false},{"pmid":"16935389","id":"PMC_16935389","title":"Deregulation of the activin/follistatin system in hepatocarcinogenesis.","date":"2006","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/16935389","citation_count":56,"is_preprint":false},{"pmid":"9426975","id":"PMC_9426975","title":"Production of activin A and its roles in inflammation and hematopoiesis.","date":"1997","source":"Cytokines, cellular & molecular therapy","url":"https://pubmed.ncbi.nlm.nih.gov/9426975","citation_count":55,"is_preprint":false},{"pmid":"10918299","id":"PMC_10918299","title":"Regulation of activin's access to the cell: why is mother nature such a control freak?","date":"2000","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/10918299","citation_count":55,"is_preprint":false},{"pmid":"19095948","id":"PMC_19095948","title":"Activin C antagonizes activin A in vitro and overexpression leads to pathologies in vivo.","date":"2008","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19095948","citation_count":55,"is_preprint":false},{"pmid":"14979665","id":"PMC_14979665","title":"Regulation of BMP and activin signaling in Drosophila.","date":"2004","source":"Progress in molecular and subcellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14979665","citation_count":53,"is_preprint":false},{"pmid":"22761777","id":"PMC_22761777","title":"Effects of activin and TGFβ on p21 in colon cancer.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22761777","citation_count":52,"is_preprint":false},{"pmid":"33933900","id":"PMC_33933900","title":"Principles of the activin receptor signaling pathway and its inhibition.","date":"2021","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/33933900","citation_count":50,"is_preprint":false},{"pmid":"9395712","id":"PMC_9395712","title":"Follistatin and its role as an activin-binding protein.","date":"1997","source":"The journal of medical investigation : JMI","url":"https://pubmed.ncbi.nlm.nih.gov/9395712","citation_count":50,"is_preprint":false},{"pmid":"18180762","id":"PMC_18180762","title":"Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior.","date":"2008","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/18180762","citation_count":50,"is_preprint":false},{"pmid":"28468752","id":"PMC_28468752","title":"USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling.","date":"2017","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/28468752","citation_count":48,"is_preprint":false},{"pmid":"26030849","id":"PMC_26030849","title":"Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity.","date":"2015","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26030849","citation_count":48,"is_preprint":false},{"pmid":"12032389","id":"PMC_12032389","title":"The physiology and pathophysiology of inhibin, activin and follistatin in female reproduction.","date":"2002","source":"Current opinion in obstetrics & gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/12032389","citation_count":47,"is_preprint":false},{"pmid":"35999217","id":"PMC_35999217","title":"Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35999217","citation_count":46,"is_preprint":false},{"pmid":"29739878","id":"PMC_29739878","title":"BMPR2 inhibits activin and BMP signaling via wild-type ALK2.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/29739878","citation_count":46,"is_preprint":false},{"pmid":"32150356","id":"PMC_32150356","title":"A paracrine activin A-mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming.","date":"2020","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32150356","citation_count":46,"is_preprint":false},{"pmid":"11117535","id":"PMC_11117535","title":"Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling.","date":"2000","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/11117535","citation_count":46,"is_preprint":false},{"pmid":"11261590","id":"PMC_11261590","title":"Activin receptors are expressed on human lung fibroblast and activin A facilitates fibroblast-mediated collagen gel contraction.","date":"2000","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/11261590","citation_count":46,"is_preprint":false},{"pmid":"19615428","id":"PMC_19615428","title":"Regulation of osteoblastogenesis and osteoclastogenesis by the other reproductive hormones, Activin and Inhibin.","date":"2009","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19615428","citation_count":45,"is_preprint":false},{"pmid":"32235336","id":"PMC_32235336","title":"Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors.","date":"2020","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/32235336","citation_count":45,"is_preprint":false},{"pmid":"15027884","id":"PMC_15027884","title":"Inhibin/activin and ovarian cancer.","date":"2004","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15027884","citation_count":43,"is_preprint":false},{"pmid":"8323185","id":"PMC_8323185","title":"Inhibin, activin, and follistatin. Potential roles in ovarian physiology.","date":"1993","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8323185","citation_count":43,"is_preprint":false},{"pmid":"18407237","id":"PMC_18407237","title":"Inhibin and activin Molecular aspects of regulation and function.","date":"1994","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/18407237","citation_count":43,"is_preprint":false},{"pmid":"27020852","id":"PMC_27020852","title":"Inhibition of Activin Signaling Slows Progression of Polycystic Kidney Disease.","date":"2016","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/27020852","citation_count":43,"is_preprint":false},{"pmid":"11911962","id":"PMC_11911962","title":"Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan.","date":"2002","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11911962","citation_count":42,"is_preprint":false},{"pmid":"12469187","id":"PMC_12469187","title":"Clinical significance of the expression of activin A in esophageal carcinoma.","date":"2003","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12469187","citation_count":42,"is_preprint":false},{"pmid":"35896531","id":"PMC_35896531","title":"Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35896531","citation_count":40,"is_preprint":false},{"pmid":"15471966","id":"PMC_15471966","title":"Heparin and activin-binding determinants in follistatin and FSTL3.","date":"2004","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15471966","citation_count":40,"is_preprint":false},{"pmid":"23024260","id":"PMC_23024260","title":"Activin A stimulates AKR1C3 expression and growth in human prostate cancer.","date":"2012","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23024260","citation_count":40,"is_preprint":false},{"pmid":"18460206","id":"PMC_18460206","title":"The glycoprotein-hormones activin A and inhibin A interfere with dendritic cell maturation.","date":"2008","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/18460206","citation_count":40,"is_preprint":false},{"pmid":"27922109","id":"PMC_27922109","title":"Regulation of hepcidin expression by inflammation-induced activin B.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27922109","citation_count":39,"is_preprint":false},{"pmid":"11451590","id":"PMC_11451590","title":"Involvement of activin in the regulation of bone metabolism.","date":"2001","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11451590","citation_count":39,"is_preprint":false},{"pmid":"10320478","id":"PMC_10320478","title":"Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals.","date":"1999","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/10320478","citation_count":38,"is_preprint":false},{"pmid":"15451563","id":"PMC_15451563","title":"Modulation of activin and BMP signaling.","date":"2004","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15451563","citation_count":36,"is_preprint":false},{"pmid":"15451561","id":"PMC_15451561","title":"Novel factors in regulation of activin signaling.","date":"2004","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15451561","citation_count":36,"is_preprint":false},{"pmid":"32878730","id":"PMC_32878730","title":"Wound Repair, Scar Formation, and Cancer: Converging on Activin.","date":"2020","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32878730","citation_count":35,"is_preprint":false},{"pmid":"11786387","id":"PMC_11786387","title":"Production and purification of recombinant human inhibin and activin.","date":"2002","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11786387","citation_count":35,"is_preprint":false},{"pmid":"7999062","id":"PMC_7999062","title":"Demonstration of activin-A in arteriosclerotic lesions.","date":"1994","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7999062","citation_count":35,"is_preprint":false},{"pmid":"17680997","id":"PMC_17680997","title":"The neuroprotective effect of Activin A and B: implication for neurodegenerative diseases.","date":"2007","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17680997","citation_count":35,"is_preprint":false},{"pmid":"11451568","id":"PMC_11451568","title":"Intracellular and extracellular control of activin function by novel regulatory molecules.","date":"2001","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11451568","citation_count":34,"is_preprint":false},{"pmid":"26869672","id":"PMC_26869672","title":"Activin-A is overexpressed in severe asthma and is implicated in angiogenic processes.","date":"2016","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/26869672","citation_count":33,"is_preprint":false},{"pmid":"7958751","id":"PMC_7958751","title":"Activin-like peptides in somatotrophs and activin stimulation of growth hormone release in goldfish.","date":"1994","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/7958751","citation_count":33,"is_preprint":false},{"pmid":"22563507","id":"PMC_22563507","title":"R-Smad competition controls activin receptor output in Drosophila.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22563507","citation_count":32,"is_preprint":false},{"pmid":"27932444","id":"PMC_27932444","title":"Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages.","date":"2017","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27932444","citation_count":31,"is_preprint":false},{"pmid":"1966558","id":"PMC_1966558","title":"Activin as a cell differentiation factor.","date":"1990","source":"Progress in growth factor research","url":"https://pubmed.ncbi.nlm.nih.gov/1966558","citation_count":31,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44537,"output_tokens":1031,"usd":0.074538},"stage2":{"model":"claude-opus-4-6","input_tokens":4244,"output_tokens":2630,"usd":0.130455},"total_usd":0.204993,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"Heterozygous protein-truncating mutations in INHBE (encoding the hepatokine activin E) associate with favorable fat distribution (lower waist-to-hip ratio) and ~28% lower odds of type 2 diabetes; the most common pLOF variant causes an in-frame deletion resulting in 90% reduction in secreted activin E protein, establishing INHBE as a liver-expressed negative regulator of adipose storage.\",\n      \"method\": \"Exome sequencing in 618,375 individuals combined with in vitro characterization of pLOF variant showing reduced secreted protein levels\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large-scale human genetics (exome-wide) replicated across multiple cohorts plus in vitro functional characterization of protein secretion\",\n      \"pmids\": [\"35999217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Predicted loss-of-function variants in INHBE associate with lower waist-to-hip ratio adjusted for BMI; additionally, variants in ACVR1C (encoding an activin receptor) show the same association, further indicating that the activin E–ACVR1C signaling axis regulates abdominal fat distribution.\",\n      \"method\": \"Exome sequencing in 362,679 individuals with replication in AMP-T2D-GENES; in vitro characterization of the most common pLOF variant showing 90% reduction in secreted protein\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across independent cohorts with functional validation of reduced protein secretion\",\n      \"pmids\": [\"35896531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of activin βE (the INHBE-encoded subunit) in mouse liver via nonviral gene transfer temporarily inhibited regenerative DNA synthesis in hepatocytes and non-parenchymal cells, demonstrating that activin E has a growth-inhibitory biological activity in liver tissue homeostasis.\",\n      \"method\": \"In vivo nonviral hydrodynamic gene transfer to mouse liver, mRNA analysis, reporter gene co-expression, measurement of DNA synthesis during liver regeneration\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo loss-of-function/gain-of-function with quantitative DNA synthesis readout, single lab\",\n      \"pmids\": [\"12865331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Activin βE (INHBE product) is expressed in hepatocytes and is downregulated in rat and human liver tumors; follistatin administration stimulated DNA synthesis preferentially in preneoplastic hepatocytes while activin A repressed it, consistent with activin E functioning as part of a growth-suppressive activin/follistatin balance in the liver.\",\n      \"method\": \"Real-time PCR, immunohistochemistry in chemically induced rat and human liver tumors; DNA synthesis assays with follistatin and activin A treatment\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — expression and functional data from the same lab, single study; functional read-out used activin A as proxy for the activin/follistatin axis\",\n      \"pmids\": [\"16935389\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INHBE encodes activin E (inhibin βE), a hepatocyte-secreted member of the activin family that acts as a circulating negative regulator of adipose fat storage; human loss-of-function mutations that reduce secreted activin E levels are associated with favorable fat distribution and protection from type 2 diabetes, while liver-directed overexpression studies in mice show that activin E inhibits hepatocyte DNA synthesis, implicating it in liver growth homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"INHBE encodes activin βE, a liver-expressed secreted member of the TGF-β/activin family that functions as a hepatokine regulating both adipose fat storage and hepatocyte proliferation. In human genetics studies, heterozygous protein-truncating variants in INHBE—which reduce secreted activin E protein by ~90%—associate with favorable fat distribution (lower waist-to-hip ratio) and ~28% reduced odds of type 2 diabetes, and convergent loss-of-function associations in the receptor gene ACVR1C confirm that the activin E–ACVR1C signaling axis governs abdominal adiposity [PMID:35999217, PMID:35896531]. Overexpression of activin βE in mouse liver inhibits regenerative DNA synthesis in hepatocytes, and activin βE is downregulated in rat and human liver tumors, indicating an additional growth-suppressive role in liver tissue homeostasis [PMID:12865331, PMID:16935389].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether activin βE has any biological activity was unknown; liver-directed overexpression demonstrated that it inhibits hepatocyte DNA synthesis during regeneration, establishing activin E as a growth-inhibitory factor in the liver.\",\n      \"evidence\": \"In vivo nonviral hydrodynamic gene transfer to mouse liver with measurement of DNA synthesis during liver regeneration\",\n      \"pmids\": [\"12865331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single gain-of-function approach without genetic loss-of-function confirmation in vivo\",\n        \"Whether endogenous activin E levels are sufficient to regulate liver regeneration was not tested\",\n        \"Receptor and downstream signaling pathway mediating the growth-inhibitory effect were not identified\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The relevance of activin βE to liver pathology was unclear; demonstration that INHBE is expressed in hepatocytes and downregulated in liver tumors positioned activin E within the growth-suppressive activin/follistatin axis in hepatocarcinogenesis.\",\n      \"evidence\": \"Real-time PCR and immunohistochemistry in chemically induced rat liver tumors and human liver tumors; DNA synthesis assays with follistatin and activin A\",\n      \"pmids\": [\"16935389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Growth-suppressive effects were demonstrated with activin A, not activin E directly, so the specific contribution of activin E to tumor suppression remains inferred\",\n        \"No genetic manipulation of INHBE in tumor models\",\n        \"Mechanism of INHBE downregulation in tumors was not elucidated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether activin E has systemic metabolic functions was unknown; large-scale human exome studies revealed that INHBE loss-of-function variants confer favorable fat distribution and protection from type 2 diabetes, and concordant findings in the receptor gene ACVR1C established an activin E–ACVR1C signaling axis governing abdominal adiposity.\",\n      \"evidence\": \"Exome sequencing in >600,000 individuals across multiple cohorts with replication; in vitro characterization showing ~90% reduction in secreted protein for the most common pLOF variant\",\n      \"pmids\": [\"35999217\", \"35896531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct demonstration of activin E signaling through ACVR1C at the biochemical level has not been shown\",\n        \"Mechanism by which reduced circulating activin E alters adipose tissue biology is unknown\",\n        \"No animal loss-of-function model has confirmed the metabolic phenotype\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the precise receptor complex engaged by activin E homodimers or heterodimers, the intracellular signaling cascade (Smad versus non-Smad) in adipocytes, and whether the liver growth-suppressive and metabolic roles are mediated through the same or distinct pathways.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal structure or binding affinity data for activin E with type I/II receptors\",\n        \"No conditional knockout or knockdown model in liver or adipose tissue\",\n        \"Whether activin E acts as homodimer or heterodimer with other β subunits in vivo is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ACVR1C\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway term_id. Let me correct that:\n\n```json\n{\n  \"mechanistic_narrative\": \"INHBE encodes activin βE, a liver-expressed secreted member of the TGF-β/activin family that functions as a hepatokine regulating both adipose fat storage and hepatocyte proliferation. In human genetics studies, heterozygous protein-truncating variants in INHBE—which reduce secreted activin E protein by ~90%—associate with favorable fat distribution (lower waist-to-hip ratio) and ~28% reduced odds of type 2 diabetes, and convergent loss-of-function associations in the receptor gene ACVR1C confirm that the activin E–ACVR1C signaling axis governs abdominal adiposity [PMID:35999217, PMID:35896531]. Overexpression of activin βE in mouse liver inhibits regenerative DNA synthesis in hepatocytes, and activin βE is downregulated in rat and human liver tumors, indicating an additional growth-suppressive role in liver tissue homeostasis [PMID:12865331, PMID:16935389].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether activin βE has any biological activity was unknown; liver-directed overexpression demonstrated that it inhibits hepatocyte DNA synthesis during regeneration, establishing activin E as a growth-inhibitory factor in the liver.\",\n      \"evidence\": \"In vivo nonviral hydrodynamic gene transfer to mouse liver with measurement of DNA synthesis during liver regeneration\",\n      \"pmids\": [\"12865331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single gain-of-function approach without genetic loss-of-function confirmation in vivo\",\n        \"Whether endogenous activin E levels are sufficient to regulate liver regeneration was not tested\",\n        \"Receptor and downstream signaling pathway mediating the growth-inhibitory effect were not identified\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The relevance of activin βE to liver pathology was unclear; demonstration that INHBE is expressed in hepatocytes and downregulated in liver tumors positioned activin E within the growth-suppressive activin/follistatin axis in hepatocarcinogenesis.\",\n      \"evidence\": \"Real-time PCR and immunohistochemistry in chemically induced rat liver tumors and human liver tumors; DNA synthesis assays with follistatin and activin A\",\n      \"pmids\": [\"16935389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Growth-suppressive effects were demonstrated with activin A, not activin E directly, so the specific contribution of activin E to tumor suppression remains inferred\",\n        \"No genetic manipulation of INHBE in tumor models\",\n        \"Mechanism of INHBE downregulation in tumors was not elucidated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether activin E has systemic metabolic functions was unknown; large-scale human exome studies revealed that INHBE loss-of-function variants confer favorable fat distribution and protection from type 2 diabetes, and concordant findings in the receptor gene ACVR1C established an activin E–ACVR1C signaling axis governing abdominal adiposity.\",\n      \"evidence\": \"Exome sequencing in >600,000 individuals across multiple cohorts with replication; in vitro characterization showing ~90% reduction in secreted protein for the most common pLOF variant\",\n      \"pmids\": [\"35999217\", \"35896531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct demonstration of activin E signaling through ACVR1C at the biochemical level has not been shown\",\n        \"Mechanism by which reduced circulating activin E alters adipose tissue biology is unknown\",\n        \"No animal loss-of-function model has confirmed the metabolic phenotype\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the precise receptor complex engaged by activin E, the intracellular signaling cascade in adipocytes, and whether the liver growth-suppressive and metabolic roles are mediated through the same or distinct pathways.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal structure or binding affinity data for activin E with type I/II receptors\",\n        \"No conditional knockout or knockdown model in liver or adipose tissue\",\n        \"Whether activin E acts as homodimer or heterodimer with other β subunits in vivo is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ACVR1C\"],\n    \"other_free_text\": []\n  }\n}\n```"}