{"gene":"INHBE","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2022,"finding":"INHBE encodes a secreted hepatokine called activin E, which is highly and specifically expressed in hepatocytes. In vitro characterization of the most common predicted loss-of-function (pLOF) variant in INHBE (an in-frame deletion) demonstrated approximately 90% reduction in secreted protein levels, establishing that this variant impairs protein secretion. Genetic association of pLOF variants in INHBE with lower waist-to-hip ratio adjusted for BMI (WHRadjBMI) and with lower odds of type 2 diabetes (~28%) identifies INHBE as a liver-expressed negative regulator of adipose storage.","method":"Exome sequencing (618,375 individuals) combined with in vitro functional characterization of pLOF variant showing reduced secreted protein; genetic association with ACVR1C (activin receptor) variants corroborating pathway","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale human genetics plus in vitro secretion assay for the specific variant; single lab functional follow-up with one method for the mechanistic characterization","pmids":["35999217"],"is_preprint":false},{"year":2022,"finding":"Rare predicted loss-of-function (pLOF) variants in INHBE associate with lower waist-to-hip ratio adjusted for BMI (WHRadjBMI) and protection from abdominal obesity, with replication in the AMP-T2D-GENES dataset. The association signal for WHRadjBMI was also found for variants in ACVR1C (encoding an activin receptor), indicating that activin E signals through ACVR1C to regulate fat distribution. INHBE is established as a hepatokine whose loss reduces abdominal fat accumulation.","method":"Exome sequencing in 362,679 individuals with replication cohort; genetic epistasis via parallel ACVR1C association implicating receptor pathway","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale human exome study replicated in independent cohort, pathway placement via ACVR1C association, but no direct biochemical reconstitution of INHBE-ACVR1C interaction","pmids":["35896531"],"is_preprint":false},{"year":2006,"finding":"The activin βE subunit (INHBE) is highly expressed in hepatocytes and shows down-regulation in liver tumors. A growth-inhibitory function similar to activin βA (activin A) has been demonstrated for the βE subunit in the liver context, suggesting INHBE participates in regulating hepatocyte proliferation.","method":"Expression analysis and functional studies in liver tumor models (referenced as growth inhibitory function shown for βE)","journal":"Mutation research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper summarizing prior experimental findings for βE with limited methodological detail in the abstract; single indirect reference to growth inhibitory function","pmids":["16997617"],"is_preprint":false},{"year":2005,"finding":"In rat liver regeneration, activin βE mRNA expression (along with βA and βC) is upregulated in the postoperative early stage following both partial hepatectomy and portal vein branch ligation, with expression levels differing between the two models. This correlates inversely with hepatocyte proliferation (PCNA labeling index), consistent with a role for βE in regulating hepatocyte proliferation during liver regeneration.","method":"RT-PCR measurement of activin subunit mRNA expression combined with PCNA labeling index in rat liver regeneration models (partial hepatectomy vs. portal vein branch ligation)","journal":"The Journal of surgical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative mRNA expression data without direct functional manipulation of INHBE specifically","pmids":["15916968"],"is_preprint":false}],"current_model":"INHBE encodes activin E, a secreted hepatokine specifically and highly expressed in hepatocytes; predicted loss-of-function variants that reduce secreted protein levels by ~90% are associated in large human exome studies with favorable abdominal fat distribution and protection from type 2 diabetes, and parallel associations with ACVR1C (an activin type I receptor) suggest activin E signals through ACVR1C to negatively regulate adipose storage, positioning INHBE as a liver-derived negative regulator of fat distribution."},"narrative":{"mechanistic_narrative":"INHBE encodes activin E, a secreted hepatokine highly and specifically expressed in hepatocytes that functions as a liver-derived negative regulator of adipose storage [PMID:35999217]. Large-scale human exome studies link rare predicted loss-of-function variants in INHBE to lower waist-to-hip ratio adjusted for BMI and reduced odds of type 2 diabetes, and in vitro the most common pLOF variant cuts secreted protein levels by roughly 90%, establishing that these variants act by impairing secretion [PMID:35999217]. Parallel association of WHRadjBMI signals with variants in the activin receptor ACVR1C places activin E upstream of ACVR1C in a signaling axis controlling fat distribution [PMID:35896531]. In the liver itself, the activin βE subunit is implicated in regulating hepatocyte proliferation, being upregulated early in liver regeneration models inversely with proliferation indices and down-regulated in liver tumors [PMID:15916968, PMID:16997617]. Beyond this human-genetic pathway placement and correlative hepatic expression data, no direct biochemical reconstitution of the activin E–ACVR1C interaction has been characterized in the available corpus.","teleology":[{"year":2005,"claim":"Whether the activin βE subunit has any regulated role in liver biology was unestablished; measuring its expression during regeneration tied it to hepatocyte proliferation control.","evidence":"RT-PCR of activin subunit mRNA with PCNA labeling in rat partial hepatectomy and portal vein ligation models","pmids":["15916968"],"confidence":"Low","gaps":["Correlative mRNA only, no direct functional manipulation of INHBE","Rat model; human relevance not addressed","No receptor or downstream mechanism defined"]},{"year":2006,"claim":"Building on regeneration data, the βE subunit was linked to growth inhibition in the liver and to dysregulation in liver tumors, suggesting a tumor-suppressive proliferation-restraining role.","evidence":"Expression analysis and functional summary in liver tumor models (review)","pmids":["16997617"],"confidence":"Low","gaps":["Review-level summary with limited methodological detail","Growth-inhibitory effect not mechanistically dissected for βE specifically","No secreted-protein or receptor data"]},{"year":2022,"claim":"Whether INHBE has a systemic metabolic function in humans was unknown; large exome studies established it as a hepatokine whose loss-of-function protects against abdominal obesity and type 2 diabetes, and an in vitro secretion assay showed the common pLOF variant impairs protein secretion.","evidence":"Exome sequencing of 618,375 individuals with in vitro characterization of the in-frame deletion pLOF variant showing ~90% reduced secretion","pmids":["35999217"],"confidence":"Medium","gaps":["Single-lab functional follow-up with one secretion assay","Mechanism of how reduced activin E lowers adipose storage not demonstrated biochemically","No in vivo demonstration of the metabolic effect"]},{"year":2022,"claim":"To place activin E in a signaling pathway, parallel association of WHRadjBMI with ACVR1C variants implicated the activin type I receptor ACVR1C as the relevant receptor, indicating activin E signals through ACVR1C to regulate fat distribution.","evidence":"Exome sequencing of 362,679 individuals with independent replication and parallel ACVR1C genetic association","pmids":["35896531"],"confidence":"Medium","gaps":["Pathway inferred from genetic co-association, not direct INHBE–ACVR1C binding","Downstream signaling effectors in adipose tissue not defined","Cell type mediating the receptor effect not identified"]},{"year":null,"claim":"Direct biochemical demonstration of activin E binding and activating ACVR1C, and the downstream signaling that links the hepatokine to adipose storage, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted activin E–ACVR1C interaction","Downstream signaling cascade in adipocytes uncharacterized","Mechanistic basis for protection from type 2 diabetes not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":[],"partners":["ACVR1C"],"other_free_text":[]}},"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":"1646080","id":"PMC_1646080","title":"Expression cloning of an activin receptor, a predicted transmembrane serine kinase.","date":"1991","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1646080","citation_count":712,"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":360,"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":255,"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":201,"is_preprint":false},{"pmid":"8149920","id":"PMC_8149920","title":"Activin-mediated mesoderm induction requires FGF.","date":"1994","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8149920","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":"10921901","id":"PMC_10921901","title":"Activin receptor patterning of foregut organogenesis.","date":"2000","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10921901","citation_count":155,"is_preprint":false},{"pmid":"10996525","id":"PMC_10996525","title":"Activin signal transduction pathways.","date":"2000","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/10996525","citation_count":154,"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":153,"is_preprint":false},{"pmid":"25670788","id":"PMC_25670788","title":"Activin/Nodal signalling in stem cells.","date":"2015","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25670788","citation_count":142,"is_preprint":false},{"pmid":"21353885","id":"PMC_21353885","title":"The regulation and functions of activin and follistatin in inflammation and immunity.","date":"2011","source":"Vitamins and hormones","url":"https://pubmed.ncbi.nlm.nih.gov/21353885","citation_count":142,"is_preprint":false},{"pmid":"27376469","id":"PMC_27376469","title":"Activin A programs the differentiation of human TFH cells.","date":"2016","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27376469","citation_count":140,"is_preprint":false},{"pmid":"19261538","id":"PMC_19261538","title":"Activin and related proteins in inflammation: not just interested bystanders.","date":"2009","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/19261538","citation_count":131,"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":131,"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":"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":110,"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":"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":"9892009","id":"PMC_9892009","title":"Roles of pathway-specific and inhibitory Smads in activin receptor signaling.","date":"1999","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9892009","citation_count":92,"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":"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":"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":"10819759","id":"PMC_10819759","title":"Activin, inhibin, and follistatin in zebrafish ovary: expression and role in oocyte maturation.","date":"2000","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/10819759","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":81,"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":"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":75,"is_preprint":false},{"pmid":"10698204","id":"PMC_10698204","title":"Activin A-induced HepG2 liver cell apoptosis: involvement of activin receptors and smad proteins.","date":"2000","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10698204","citation_count":75,"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":"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":"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":"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":"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":"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":58,"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":"26497569","id":"PMC_26497569","title":"Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer.","date":"2015","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26497569","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":"17249382","id":"PMC_17249382","title":"Activin A in brain injury.","date":"2007","source":"Advances in clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17249382","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":"15451571","id":"PMC_15451571","title":"Activin, inhibin and the human breast.","date":"2004","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15451571","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":"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":49,"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":"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":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":"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":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":"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":"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":"15916968","id":"PMC_15916968","title":"Activin and activin receptor expression changes in liver regeneration in rat.","date":"2005","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/15916968","citation_count":43,"is_preprint":false},{"pmid":"11969340","id":"PMC_11969340","title":"The distribution of activin and activin receptors in gestational tissues across human pregnancy and during labour.","date":"2002","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/11969340","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":41,"is_preprint":false},{"pmid":"9987674","id":"PMC_9987674","title":"Activin: a novel player in tissue repair processes.","date":"1999","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/9987674","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":"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":"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":40,"is_preprint":false},{"pmid":"23385857","id":"PMC_23385857","title":"Activin, neutrophils, and inflammation: just coincidence?","date":"2013","source":"Seminars in immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/23385857","citation_count":38,"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":"25942106","id":"PMC_25942106","title":"Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?","date":"2015","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/25942106","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":"11451587","id":"PMC_11451587","title":"Expression of activin A in inflammatory arthropathies.","date":"2001","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11451587","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":34,"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":"32700590","id":"PMC_32700590","title":"Activin A: an emerging target for improving cancer treatment?","date":"2020","source":"Expert opinion on therapeutic targets","url":"https://pubmed.ncbi.nlm.nih.gov/32700590","citation_count":32,"is_preprint":false},{"pmid":"10638976","id":"PMC_10638976","title":"Variations in activin receptor, inhibin/activin subunit and follistatin mRNAs in human prostate tumour tissues.","date":"2000","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10638976","citation_count":32,"is_preprint":false},{"pmid":"35736809","id":"PMC_35736809","title":"The orphan ligand, activin C, signals through activin receptor-like kinase 7.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35736809","citation_count":31,"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":"21631612","id":"PMC_21631612","title":"Activin-A: a novel critical regulator of allergic asthma.","date":"2011","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21631612","citation_count":31,"is_preprint":false},{"pmid":"18606140","id":"PMC_18606140","title":"Regulation of activin/nodal signaling by Rap2-directed receptor trafficking.","date":"2008","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/18606140","citation_count":30,"is_preprint":false},{"pmid":"25349448","id":"PMC_25349448","title":"Activin/Nodal signalling before implantation: setting the stage for embryo patterning.","date":"2014","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25349448","citation_count":29,"is_preprint":false},{"pmid":"24917498","id":"PMC_24917498","title":"Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24917498","citation_count":29,"is_preprint":false},{"pmid":"35333341","id":"PMC_35333341","title":"Mechanisms of myostatin and activin A accumulation in chronic kidney disease.","date":"2022","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/35333341","citation_count":28,"is_preprint":false},{"pmid":"11149384","id":"PMC_11149384","title":"Roles of the activin regulatory system in fish reproduction.","date":"2000","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/11149384","citation_count":28,"is_preprint":false},{"pmid":"17827789","id":"PMC_17827789","title":"Activin A: autocrine regulator of kidney development and repair.","date":"2007","source":"Endocrine journal","url":"https://pubmed.ncbi.nlm.nih.gov/17827789","citation_count":26,"is_preprint":false},{"pmid":"32553795","id":"PMC_32553795","title":"Activin A does not drive post-traumatic heterotopic ossification.","date":"2020","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/32553795","citation_count":26,"is_preprint":false},{"pmid":"11746957","id":"PMC_11746957","title":"Localization of an activin/activin receptor system in the porcine ovary.","date":"2001","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/11746957","citation_count":25,"is_preprint":false},{"pmid":"10098513","id":"PMC_10098513","title":"Activin and inhibin binding to the soluble extracellular domain of activin receptor II.","date":"1999","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10098513","citation_count":25,"is_preprint":false},{"pmid":"12706302","id":"PMC_12706302","title":"Changes in activin and activin receptor subunit expression in rat liver during the development of CCl4-induced cirrhosis.","date":"2003","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/12706302","citation_count":25,"is_preprint":false},{"pmid":"16648306","id":"PMC_16648306","title":"Characterization of isoforms of activin receptor-interacting protein 2 that augment activin signaling.","date":"2006","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/16648306","citation_count":25,"is_preprint":false},{"pmid":"8971337","id":"PMC_8971337","title":"Activin receptors: cellular signalling by receptor serine kinases.","date":"1996","source":"Biochemical Society symposium","url":"https://pubmed.ncbi.nlm.nih.gov/8971337","citation_count":24,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44129,"output_tokens":1562,"usd":0.077909,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7874,"output_tokens":1804,"usd":0.042235,"stage2_stop_reason":"end_turn"},"total_usd":0.120144,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through these abstracts, I need to identify papers that describe mechanistic findings specifically about INHBE (inhibin βE / activin E), not just activin A/B/C or the general activin signaling pathway.\n\nKey papers about INHBE specifically:\n- PMID 35999217 (Akbari et al. 2022): INHBE encodes a circulating hepatokine (activin E), loss-of-function variants associate with favorable fat distribution; identifies it as liver-expressed\n- PMID 35896531 (Deaton et al. 2022): INHBE encodes secreted hepatokine activin E; in vitro characterization of a pLOF variant showing 90% reduction in secreted protein; association with WHRadjBMI and ACVR1C receptor\n- PMID 24917498: mentions activin betaE but in context of liver regeneration (PMID 15916968 - Takamura et al.)\n- PMID 19095948 (Gold et al. 2008): mentions activin C antagonizing activin A, but also references betaE in liver\n- PMID 16997617 (Rodgarkia-Dara et al. 2006): mentions betaE expressed in hepatocytes, down-regulation in liver tumors, growth inhibitory function\n\nMost of the corpus is about activin A (INHBA) or general activin signaling, not specifically INHBE. Only a few papers contain mechanistic data about INHBE itself.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"INHBE encodes a secreted hepatokine called activin E, which is highly and specifically expressed in hepatocytes. In vitro characterization of the most common predicted loss-of-function (pLOF) variant in INHBE (an in-frame deletion) demonstrated approximately 90% reduction in secreted protein levels, establishing that this variant impairs protein secretion. Genetic association of pLOF variants in INHBE with lower waist-to-hip ratio adjusted for BMI (WHRadjBMI) and with lower odds of type 2 diabetes (~28%) identifies INHBE as a liver-expressed negative regulator of adipose storage.\",\n      \"method\": \"Exome sequencing (618,375 individuals) combined with in vitro functional characterization of pLOF variant showing reduced secreted protein; genetic association with ACVR1C (activin receptor) variants corroborating pathway\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale human genetics plus in vitro secretion assay for the specific variant; single lab functional follow-up with one method for the mechanistic characterization\",\n      \"pmids\": [\"35999217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rare predicted loss-of-function (pLOF) variants in INHBE associate with lower waist-to-hip ratio adjusted for BMI (WHRadjBMI) and protection from abdominal obesity, with replication in the AMP-T2D-GENES dataset. The association signal for WHRadjBMI was also found for variants in ACVR1C (encoding an activin receptor), indicating that activin E signals through ACVR1C to regulate fat distribution. INHBE is established as a hepatokine whose loss reduces abdominal fat accumulation.\",\n      \"method\": \"Exome sequencing in 362,679 individuals with replication cohort; genetic epistasis via parallel ACVR1C association implicating receptor pathway\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale human exome study replicated in independent cohort, pathway placement via ACVR1C association, but no direct biochemical reconstitution of INHBE-ACVR1C interaction\",\n      \"pmids\": [\"35896531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The activin βE subunit (INHBE) is highly expressed in hepatocytes and shows down-regulation in liver tumors. A growth-inhibitory function similar to activin βA (activin A) has been demonstrated for the βE subunit in the liver context, suggesting INHBE participates in regulating hepatocyte proliferation.\",\n      \"method\": \"Expression analysis and functional studies in liver tumor models (referenced as growth inhibitory function shown for βE)\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper summarizing prior experimental findings for βE with limited methodological detail in the abstract; single indirect reference to growth inhibitory function\",\n      \"pmids\": [\"16997617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In rat liver regeneration, activin βE mRNA expression (along with βA and βC) is upregulated in the postoperative early stage following both partial hepatectomy and portal vein branch ligation, with expression levels differing between the two models. This correlates inversely with hepatocyte proliferation (PCNA labeling index), consistent with a role for βE in regulating hepatocyte proliferation during liver regeneration.\",\n      \"method\": \"RT-PCR measurement of activin subunit mRNA expression combined with PCNA labeling index in rat liver regeneration models (partial hepatectomy vs. portal vein branch ligation)\",\n      \"journal\": \"The Journal of surgical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative mRNA expression data without direct functional manipulation of INHBE specifically\",\n      \"pmids\": [\"15916968\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INHBE encodes activin E, a secreted hepatokine specifically and highly expressed in hepatocytes; predicted loss-of-function variants that reduce secreted protein levels by ~90% are associated in large human exome studies with favorable abdominal fat distribution and protection from type 2 diabetes, and parallel associations with ACVR1C (an activin type I receptor) suggest activin E signals through ACVR1C to negatively regulate adipose storage, positioning INHBE as a liver-derived negative regulator of fat distribution.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INHBE encodes activin E, a secreted hepatokine highly and specifically expressed in hepatocytes that functions as a liver-derived negative regulator of adipose storage [#0]. Large-scale human exome studies link rare predicted loss-of-function variants in INHBE to lower waist-to-hip ratio adjusted for BMI and reduced odds of type 2 diabetes, and in vitro the most common pLOF variant cuts secreted protein levels by roughly 90%, establishing that these variants act by impairing secretion [#0]. Parallel association of WHRadjBMI signals with variants in the activin receptor ACVR1C places activin E upstream of ACVR1C in a signaling axis controlling fat distribution [#1]. In the liver itself, the activin \\u03b2E subunit is implicated in regulating hepatocyte proliferation, being upregulated early in liver regeneration models inversely with proliferation indices and down-regulated in liver tumors [#3, #2]. Beyond this human-genetic pathway placement and correlative hepatic expression data, no direct biochemical reconstitution of the activin E\\u2013ACVR1C interaction has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Whether the activin \\u03b2E subunit has any regulated role in liver biology was unestablished; measuring its expression during regeneration tied it to hepatocyte proliferation control.\",\n      \"evidence\": \"RT-PCR of activin subunit mRNA with PCNA labeling in rat partial hepatectomy and portal vein ligation models\",\n      \"pmids\": [\"15916968\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative mRNA only, no direct functional manipulation of INHBE\", \"Rat model; human relevance not addressed\", \"No receptor or downstream mechanism defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Building on regeneration data, the \\u03b2E subunit was linked to growth inhibition in the liver and to dysregulation in liver tumors, suggesting a tumor-suppressive proliferation-restraining role.\",\n      \"evidence\": \"Expression analysis and functional summary in liver tumor models (review)\",\n      \"pmids\": [\"16997617\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Review-level summary with limited methodological detail\", \"Growth-inhibitory effect not mechanistically dissected for \\u03b2E specifically\", \"No secreted-protein or receptor data\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether INHBE has a systemic metabolic function in humans was unknown; large exome studies established it as a hepatokine whose loss-of-function protects against abdominal obesity and type 2 diabetes, and an in vitro secretion assay showed the common pLOF variant impairs protein secretion.\",\n      \"evidence\": \"Exome sequencing of 618,375 individuals with in vitro characterization of the in-frame deletion pLOF variant showing ~90% reduced secretion\",\n      \"pmids\": [\"35999217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional follow-up with one secretion assay\", \"Mechanism of how reduced activin E lowers adipose storage not demonstrated biochemically\", \"No in vivo demonstration of the metabolic effect\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"To place activin E in a signaling pathway, parallel association of WHRadjBMI with ACVR1C variants implicated the activin type I receptor ACVR1C as the relevant receptor, indicating activin E signals through ACVR1C to regulate fat distribution.\",\n      \"evidence\": \"Exome sequencing of 362,679 individuals with independent replication and parallel ACVR1C genetic association\",\n      \"pmids\": [\"35896531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway inferred from genetic co-association, not direct INHBE\\u2013ACVR1C binding\", \"Downstream signaling effectors in adipose tissue not defined\", \"Cell type mediating the receptor effect not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Direct biochemical demonstration of activin E binding and activating ACVR1C, and the downstream signaling that links the hepatokine to adipose storage, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted activin E\\u2013ACVR1C interaction\", \"Downstream signaling cascade in adipocytes uncharacterized\", \"Mechanistic basis for protection from type 2 diabetes not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ACVR1C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}