{"gene":"ERFE","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2012,"finding":"Myonectin (CTRP15/ERFE) is a skeletal muscle-secreted myokine that forms disulfide-linked oligomers and heteromeric complexes with other CTRP family members in vitro. Recombinant myonectin administration reduced circulating free fatty acids in mice by promoting fatty acid uptake in adipocytes and hepatocytes, in part by upregulating CD36, FATP1, Fabp1, and Fabp4 expression, without altering adipose tissue lipolysis.","method":"Recombinant protein administration in mice, in vitro fatty acid uptake assays in cultured adipocytes/hepatocytes, gene expression analysis, co-expression studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo recombinant protein experiment plus in vitro cellular assays, single lab, multiple complementary methods","pmids":["22351773"],"is_preprint":false},{"year":2019,"finding":"ERFE functions as a secreted BMP pathway antagonist; it inhibits BMP signaling at the extracellular level by interacting directly with BMP ligands, and this activity does not require the conserved C1q domain. In Xenopus embryos, ERFE acts as a potent secondary axis-inducing agent and selective BMP pathway inhibitor, and knockdown causes vascular network defects and edema.","method":"Gain-of-function screen in Xenopus embryos, ectodermal explant assays, domain deletion experiments, ERFE morpholino knockdown, RNAseq of morphant embryos","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal in vivo and explant experiments with domain deletion establishing extracellular BMP ligand interaction mechanism, single lab","pmids":["31846624"],"is_preprint":false},{"year":2018,"finding":"ERFE acts downstream of EPO to suppress hepcidin expression by interfering with the binding of specific BMP ligands to their receptors, thereby inhibiting BMP-mediated signaling in the liver.","method":"Commentary citing experimental evidence from Arezes et al. (referenced within) demonstrating EPO→ERFE→BMP receptor binding interference","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — commentary summarizing experimental findings; the mechanistic claim is attributed to a primary study referenced within, replicated across context","pmids":["30287465"],"is_preprint":false},{"year":2019,"finding":"The ERFE-A260S variant leads to increased ERFE protein levels and impairs the BMP/SMAD pathway in hepatic cells, resulting in iron overload. Functional characterization in hepatic cell systems demonstrated that this variant acts as a modifier of iron regulation.","method":"Functional characterization of ERFE-A260S variant in hepatic cell systems, BMP/SMAD pathway analysis, patient cohort genotyping","journal":"American journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assay with pathway readout and patient genetic data, single lab, two complementary approaches","pmids":["31400017"],"is_preprint":false},{"year":2020,"finding":"CTRP15 (ERFE) produced by cardiac myocytes inhibits TGF-β1-induced Smad3 activation and myofibroblast differentiation in cardiac fibroblasts. This anti-fibrotic effect is mediated through activation of the insulin receptor (IR)/IRS-1/Akt pathway, and blockade of IR/IRS-1/Akt reverses the inhibitory effect of CTRP15 on Smad3.","method":"AAV9-mediated overexpression in pressure-overloaded mice, recombinant CTRP15 treatment of cardiac fibroblasts, conditioned medium experiments, adenovirus/siRNA knockdown, Western blotting, immunofluorescence, pathway inhibitor rescue experiments","journal":"Cardiovascular drugs and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments with pathway inhibitor rescue establishing IR/IRS-1/Akt→Smad3 mechanism, single lab, multiple orthogonal methods","pmids":["32424654"],"is_preprint":false},{"year":2022,"finding":"CTRP15 (ERFE) promotes macrophage cholesterol efflux and attenuates atherosclerosis by upregulating ABCA1 expression via a T-cadherin/miR-101-3p/ABCA1 pathway: CTRP15 upregulates T-cadherin, which decreases miR-101-3p expression, thereby de-repressing ABCA1 and facilitating reverse cholesterol transport.","method":"Lentivirus-mediated CTRP15 overexpression in apoE-/- mice, in vitro macrophage cholesterol efflux assays, miRNA and gene expression analysis","journal":"Journal of physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments with pathway dissection, single lab, multiple complementary methods","pmids":["35286626"],"is_preprint":false},{"year":2023,"finding":"ERFE expression in spleen is regulated by the EPO/STAT5 signaling pathway. In metabolic syndrome rats, reduced EPO leads to downregulation of STAT5/ERFE signaling, and restoration by CIHH treatment upregulates this pathway, subsequently downregulating hepatic hepcidin via the BMP/SMAD pathway.","method":"In vivo rat model (metabolic syndrome with/without CIHH), protein expression analysis (JAK2, STAT3, STAT5, BMP6, SMAD1), mRNA quantification of ERFE and hepcidin","journal":"Journal of trace elements in medicine and biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo correlative signaling data without direct manipulation of ERFE, single lab, indirect pathway inference","pmids":["37413927"],"is_preprint":false},{"year":2022,"finding":"Codon-optimized FAM132b (ERFE) with mutations A136T and P159A, delivered by AAV9, improved glucose intolerance and insulin resistance in high-fat diet mice. Structural analysis predicted the mutant may interact with β2 adrenergic receptor (ADRB2) and insulin/insulin-receptor complexes. FAM132b knockdown by shRNA increased glycemic response to epinephrine and reduced adipocyte response to epinephrine and adipose tissue browning.","method":"AAV9 gene delivery in high-fat diet mice, shRNA knockdown in vivo, structural biology prediction, in vivo metabolic phenotyping","journal":"International journal of obesity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo overexpression/KD with phenotype, receptor interaction is computational prediction only, single lab","pmids":["35922561"],"is_preprint":false},{"year":2025,"finding":"METTL14-mediated m6A methylation of ERFE mRNA stabilizes ERFE through IGF2BP3-dependent reading of the m6A mark, thereby increasing ERFE levels. In cisplatin-treated renal tubular cells, this METTL14/IGF2BP3/ERFE axis promotes ferroptosis; METTL14 knockdown attenuates ferroptosis by downregulating ERFE, while IGF2BP3 overexpression reverses this effect and ERFE depletion abrogates the reversal.","method":"MeRIP-PCR (m6A detection on ERFE mRNA), RIP assay (IGF2BP3-ERFE mRNA binding), Actinomycin D mRNA stability assay, siRNA knockdown/overexpression in HK-2 cells, ferroptosis marker quantification","journal":"Journal of trace elements in medicine and biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct m6A mapping by MeRIP-PCR, RIP assay for reader binding, mRNA stability assay, epistasis rescue experiments, single lab","pmids":["41205320"],"is_preprint":false},{"year":2024,"finding":"Osteocytes express ERFE (Fam132b) and upregulate it in response to EPO and hypoxia. Osteocyte-derived ERFE contributes to systemic hepcidin suppression during stress erythropoiesis: mice with ERFE-deficient osteocytes (bone marrow transplant model) show significantly less liver hepcidin suppression after phlebotomy. Mice lacking EPO receptors specifically in osteocytes (Epor-flox × Dmp1-Cre) also show reduced hepcidin suppression after phlebotomy.","method":"Bulk RNAseq of isolated osteocytes, bone marrow transplantation into Erfe-/- mice, conditional EPO receptor knockout in osteocytes (Epor-flox × Dmp1-Cre), phlebotomy stress model, liver hepcidin quantification","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent genetic mouse models with defined cellular readout, preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.09.27.615409"],"is_preprint":true}],"current_model":"ERFE (erythroferrone/myonectin/CTRP15/FAM132B) is a secreted C1q/TNF-family protein produced primarily by erythroid precursors and skeletal muscle (and also by osteocytes) that suppresses liver hepcidin expression by acting as an extracellular BMP ligand trap—directly binding specific BMP ligands to prevent their receptor engagement and downstream SMAD signaling—in an EPO/STAT5-regulated manner; it also promotes fatty acid uptake in liver and adipose tissue, exerts anti-fibrotic effects via IR/IRS-1/Akt→Smad3 signaling in cardiac fibroblasts, and promotes macrophage cholesterol efflux through a T-cadherin/miR-101-3p/ABCA1 axis, while its mRNA stability is post-transcriptionally regulated by METTL14-mediated m6A methylation read by IGF2BP3."},"narrative":{"mechanistic_narrative":"ERFE (erythroferrone/myonectin/CTRP15/FAM132B) is a secreted C1q/TNF-family protein that couples erythropoietic and metabolic demand to systemic iron homeostasis by acting as an extracellular BMP pathway antagonist [PMID:31846624, PMID:30287465]. Its central iron-regulatory function is to suppress liver hepcidin: acting downstream of EPO, ERFE interferes with the engagement of specific BMP ligands by their receptors, blocking BMP/SMAD signaling in the liver [PMID:30287465, PMID:37413927], and this BMP-inhibitory activity is independent of the conserved C1q domain [PMID:31846624]. ERFE is produced by multiple cell types under erythropoietic stress, including osteocytes, where EPO/EPOR signaling drives its expression and contributes to systemic hepcidin suppression after phlebotomy [PMID:bio_10.1101_2024.09.27.615409]. The gain-of-function ERFE-A260S variant raises ERFE protein, impairs hepatic BMP/SMAD signaling, and causes iron overload, establishing ERFE as a modifier of human iron regulation [PMID:31400017]. Beyond iron metabolism, ERFE has documented roles in lipid handling—promoting fatty acid uptake in adipocytes and hepatocytes via induction of CD36, FATP1, Fabp1, and Fabp4 [PMID:22351773]—and its mRNA is stabilized post-transcriptionally by METTL14-deposited m6A marks read by IGF2BP3 [PMID:41205320].","teleology":[{"year":2012,"claim":"Before its iron role was known, the protein was characterized as a muscle-secreted myokine, establishing it as a circulating C1q/TNF-family factor that influences peripheral lipid handling.","evidence":"Recombinant protein administration in mice plus in vitro fatty acid uptake assays in adipocytes/hepatocytes","pmids":["22351773"],"confidence":"Medium","gaps":["No receptor or direct binding partner identified for the fatty-acid-uptake effect","Link between lipid metabolism and later iron/BMP functions not established"]},{"year":2018,"claim":"Defined the iron-regulatory mechanism, showing ERFE acts downstream of EPO to suppress hepcidin by interfering with BMP ligand–receptor binding rather than acting as a conventional hormone on a dedicated receptor.","evidence":"Commentary summarizing experimental EPO→ERFE→BMP receptor interference data","pmids":["30287465"],"confidence":"Medium","gaps":["Identity of the specific BMP ligands trapped not resolved here","Source is a commentary, not the primary dataset"]},{"year":2019,"claim":"Established mechanistically that ERFE is an extracellular BMP antagonist acting by direct ligand binding, and mapped the activity to a region outside the conserved C1q domain.","evidence":"Gain-of-function and morpholino knockdown in Xenopus embryos, ectodermal explant assays, domain-deletion experiments, RNAseq","pmids":["31846624"],"confidence":"High","gaps":["Which BMP ligands are bound with what affinity not quantified","Structural basis of ligand sequestration unknown"]},{"year":2019,"claim":"Connected ERFE function to human disease by showing a gain-of-function variant raises ERFE, impairs hepatic BMP/SMAD signaling, and drives iron overload.","evidence":"Functional characterization of ERFE-A260S in hepatic cells with BMP/SMAD readout plus patient cohort genotyping","pmids":["31400017"],"confidence":"Medium","gaps":["Mechanism by which A260S elevates protein level unclear","Penetrance and modifier interactions in patients not defined"]},{"year":2020,"claim":"Extended ERFE biology to the heart, identifying an anti-fibrotic action mediated through IR/IRS-1/Akt signaling that antagonizes TGF-β1/Smad3, distinct from its extracellular BMP-trap mechanism.","evidence":"AAV9 overexpression in pressure-overloaded mice, recombinant protein and conditioned-medium treatment of cardiac fibroblasts, pathway inhibitor rescue","pmids":["32424654"],"confidence":"Medium","gaps":["Direct ERFE–IR binding not demonstrated","Reconciliation with BMP-trap mechanism unaddressed"]},{"year":2022,"claim":"Defined a vascular/metabolic role in which ERFE promotes macrophage cholesterol efflux through a T-cadherin/miR-101-3p/ABCA1 axis.","evidence":"Lentiviral CTRP15 overexpression in apoE-/- mice plus in vitro macrophage cholesterol efflux and miRNA/gene expression assays","pmids":["35286626"],"confidence":"Medium","gaps":["Direct interaction between ERFE and T-cadherin not shown biochemically","Relevance to iron/BMP signaling unknown"]},{"year":2022,"claim":"Implicated ERFE in glucose homeostasis, with overexpression improving insulin resistance and knockdown impairing adipose epinephrine response, though candidate receptors were only computationally predicted.","evidence":"AAV9 gene delivery and shRNA knockdown in high-fat-diet mice with metabolic phenotyping; structural prediction of ADRB2/insulin-receptor interaction","pmids":["35922561"],"confidence":"Low","gaps":["Receptor interactions (ADRB2, insulin receptor) are in silico predictions only, not experimentally validated","Mutant construct (A136T/P159A) confounds interpretation of native function"]},{"year":2023,"claim":"Provided in vivo correlative support that EPO/STAT5 governs ERFE expression and that this axis tunes hepatic hepcidin via BMP/SMAD in a metabolic-disease context.","evidence":"Rat metabolic syndrome model with/without CIHH, protein and mRNA quantification of STAT5/ERFE/hepcidin/BMP-SMAD components","pmids":["37413927"],"confidence":"Low","gaps":["No direct manipulation of ERFE; pathway linkage is correlative","STAT5 control of ERFE shown by association, not genetic perturbation"]},{"year":2024,"claim":"Identified osteocytes as an additional EPO-responsive cellular source of ERFE that contributes to systemic hepcidin suppression during stress erythropoiesis.","evidence":"Osteocyte RNAseq, bone marrow transplant into Erfe-/- mice, osteocyte-specific Epor knockout (Dmp1-Cre), phlebotomy stress model with liver hepcidin readout (preprint)","pmids":["bio_10.1101_2024.09.27.615409"],"confidence":"Medium","gaps":["Quantitative contribution of osteocyte vs erythroid ERFE not resolved","Preprint, not yet peer-reviewed"]},{"year":2025,"claim":"Revealed post-transcriptional control of ERFE, showing METTL14-deposited m6A marks read by IGF2BP3 stabilize ERFE mRNA, with functional consequences for renal tubular ferroptosis.","evidence":"MeRIP-PCR, IGF2BP3 RIP, actinomycin D mRNA stability assay, siRNA/overexpression and epistasis rescue in HK-2 cells","pmids":["41205320"],"confidence":"Medium","gaps":["Whether m6A regulation operates in erythroid/osteocyte ERFE sources untested","Mechanism linking ERFE level to ferroptosis not defined"]},{"year":null,"claim":"The molecular identity of the specific BMP ligands ERFE traps and a structural model of the ligand-binding interface remain undefined, as does how ERFE's multiple receptor-coupled effects (IR/IRS-1, T-cadherin, predicted ADRB2) relate to its extracellular BMP-antagonist mode.","evidence":"No timeline discovery resolves the ligand-binding structure or unifies the receptor-mediated mechanisms","pmids":[],"confidence":"Low","gaps":["No structural model of ERFE–BMP ligand complex","No validated cell-surface receptor for the metabolic effects","Tissue-specific selectivity among ERFE functions unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]}],"pathway":[],"complexes":[],"partners":["BMP6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q4G0M1","full_name":"Erythroferrone","aliases":["Complement C1q tumor necrosis factor-related protein 15","Myonectin"],"length_aa":354,"mass_kda":37.3,"function":"Iron-regulatory hormone that acts as an erythroid regulator after hemorrhage: produced by erythroblasts following blood loss and mediates suppression of hepcidin (HAMP) expression in the liver, thereby promoting increased iron absorption and mobilization from stores (PubMed:24880340, PubMed:30097509, PubMed:31800957). Promotes lipid uptake into adipocytes and hepatocytes via transcriptional up-regulation of genes involved in fatty acid uptake (By similarity). Inhibits apoptosis and inflammatory response in cardiomyocytes via promotion of sphingosine-1-phosphate (S1P) and cAMP-dependent activation of AKT signaling (By similarity). Inhibits autophagy induced by nutrient deficiency in hepatocytes via promoting the phosphorylation of IRS1, AKT, and MTOR, and thereby subsequent activation of the AKT-MTOR signaling pathway (By similarity). Negatively regulates the differentiation of osteoblasts, potentially via sequestering BMP2, and thereby inhibits the activation of SMAD signaling (By similarity). The reduction in BMP2 signaling in osteoblasts also results in an increase in expression of the osteoclastogenesis-promoting factors TNFSF11/RANKL and SOST, thereby indirectly promotes bone resorption (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q4G0M1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ERFE","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":77,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ERFE","total_profiled":1310},"omim":[{"mim_id":"615099","title":"ERYTHROFERRONE; ERFE","url":"https://www.omim.org/entry/615099"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skeletal muscle","ntpm":14.1},{"tissue":"testis","ntpm":12.4},{"tissue":"thyroid gland","ntpm":23.1}],"url":"https://www.proteinatlas.org/search/ERFE"},"hgnc":{"alias_symbol":["FLJ37034","CTRP15","C1QTNF15"],"prev_symbol":["FAM132B"]},"alphafold":{"accession":"Q4G0M1","domains":[{"cath_id":"2.60.120.40","chopping":"206-354","consensus_level":"high","plddt":90.3309,"start":206,"end":354}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4G0M1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q4G0M1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q4G0M1-F1-predicted_aligned_error_v6.png","plddt_mean":69.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ERFE","jax_strain_url":"https://www.jax.org/strain/search?query=ERFE"},"sequence":{"accession":"Q4G0M1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q4G0M1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q4G0M1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4G0M1"}},"corpus_meta":[{"pmid":"22351773","id":"PMC_22351773","title":"Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22351773","citation_count":309,"is_preprint":false},{"pmid":"31400017","id":"PMC_31400017","title":"The BMP-SMAD pathway mediates the impaired hepatic iron metabolism associated with the ERFE-A260S variant.","date":"2019","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/31400017","citation_count":23,"is_preprint":false},{"pmid":"32424654","id":"PMC_32424654","title":"CTRP15 derived from cardiac myocytes attenuates TGFβ1-induced fibrotic response in cardiac fibroblasts.","date":"2020","source":"Cardiovascular drugs and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32424654","citation_count":16,"is_preprint":false},{"pmid":"35286626","id":"PMC_35286626","title":"CTRP15 promotes macrophage cholesterol efflux and attenuates atherosclerosis by increasing the expression of ABCA1.","date":"2022","source":"Journal of physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35286626","citation_count":13,"is_preprint":false},{"pmid":"40036737","id":"PMC_40036737","title":"Interplay between iron metabolism, inflammation, and EPO-ERFE-hepcidin axis in RDEB-associated chronic anemia.","date":"2025","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/40036737","citation_count":8,"is_preprint":false},{"pmid":"30287465","id":"PMC_30287465","title":"A long sought after \"receptor\" for ERFE?","date":"2018","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/30287465","citation_count":6,"is_preprint":false},{"pmid":"37413927","id":"PMC_37413927","title":"Chronic intermittent hypobaric hypoxia improves iron metabolism disorders via the IL-6/JAK2/STAT3 and Epo/STAT5/ERFE signaling pathways in metabolic syndrome rats.","date":"2023","source":"Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)","url":"https://pubmed.ncbi.nlm.nih.gov/37413927","citation_count":6,"is_preprint":false},{"pmid":"38726186","id":"PMC_38726186","title":"Combined serum CTRP7 and CTRP15 levels as a novel biomarker for insulin resistance and type 2 diabetes mellitus.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38726186","citation_count":5,"is_preprint":false},{"pmid":"31846624","id":"PMC_31846624","title":"The secreted BMP antagonist ERFE is required for the development of a functional circulatory system in Xenopus.","date":"2019","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/31846624","citation_count":5,"is_preprint":false},{"pmid":"35463985","id":"PMC_35463985","title":"Effects of Different Ovulation Induction Regimens on Sex Hormone Levels and Serum CTRP3 and CTRP15 Levels in Patients with Polycystic Ovary Syndrome (PCOS).","date":"2022","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/35463985","citation_count":4,"is_preprint":false},{"pmid":"34900801","id":"PMC_34900801","title":"Increased circulating level of CTRP15 in patients with type 2 diabetes mellitus and its relation with inflammation and insulin resistance.","date":"2021","source":"Journal of diabetes and metabolic disorders","url":"https://pubmed.ncbi.nlm.nih.gov/34900801","citation_count":3,"is_preprint":false},{"pmid":"35922561","id":"PMC_35922561","title":"Codon-optimized FAM132b gene therapy prevents dietary obesity by blockading adrenergic response and insulin action.","date":"2022","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/35922561","citation_count":2,"is_preprint":false},{"pmid":"42083607","id":"PMC_42083607","title":"Expression of the FAM132B Gene in Iranian Patients with Beta-Thalassemia.","date":"2025","source":"International journal of hematology-oncology and stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/42083607","citation_count":0,"is_preprint":false},{"pmid":"41836830","id":"PMC_41836830","title":"Correlation of serum CTRP9 and CTRP15 levels with HOMA-IR and HOMA-B in metabolic syndrome patients with and without coronary artery disease.","date":"2026","source":"Pakistan journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41836830","citation_count":0,"is_preprint":false},{"pmid":"41205320","id":"PMC_41205320","title":"METTL14 promotes ferroptosis during the development of cisplatin-induced kidney injury by stabilizing ERFE through IGF2BP3-dependent m6A methylation.","date":"2025","source":"Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)","url":"https://pubmed.ncbi.nlm.nih.gov/41205320","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.27.615409","title":"Osteocyte-derived erythroferrone regulates liver hepcidin during stress erythropoiesis","date":"2024-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.27.615409","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.03.25339441","title":"<i>Veillonella atypica</i>  supplementation reduces fatigue interference and increases voluntary physical activity: A randomized controlled trial with mechanistic validation in mice","date":"2025-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.03.25339441","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12244,"output_tokens":2903,"usd":0.040139,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10283,"output_tokens":3387,"usd":0.068045,"stage2_stop_reason":"end_turn"},"total_usd":0.108184,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"Myonectin (CTRP15/ERFE) is a skeletal muscle-secreted myokine that forms disulfide-linked oligomers and heteromeric complexes with other CTRP family members in vitro. Recombinant myonectin administration reduced circulating free fatty acids in mice by promoting fatty acid uptake in adipocytes and hepatocytes, in part by upregulating CD36, FATP1, Fabp1, and Fabp4 expression, without altering adipose tissue lipolysis.\",\n      \"method\": \"Recombinant protein administration in mice, in vitro fatty acid uptake assays in cultured adipocytes/hepatocytes, gene expression analysis, co-expression studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo recombinant protein experiment plus in vitro cellular assays, single lab, multiple complementary methods\",\n      \"pmids\": [\"22351773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERFE functions as a secreted BMP pathway antagonist; it inhibits BMP signaling at the extracellular level by interacting directly with BMP ligands, and this activity does not require the conserved C1q domain. In Xenopus embryos, ERFE acts as a potent secondary axis-inducing agent and selective BMP pathway inhibitor, and knockdown causes vascular network defects and edema.\",\n      \"method\": \"Gain-of-function screen in Xenopus embryos, ectodermal explant assays, domain deletion experiments, ERFE morpholino knockdown, RNAseq of morphant embryos\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal in vivo and explant experiments with domain deletion establishing extracellular BMP ligand interaction mechanism, single lab\",\n      \"pmids\": [\"31846624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ERFE acts downstream of EPO to suppress hepcidin expression by interfering with the binding of specific BMP ligands to their receptors, thereby inhibiting BMP-mediated signaling in the liver.\",\n      \"method\": \"Commentary citing experimental evidence from Arezes et al. (referenced within) demonstrating EPO→ERFE→BMP receptor binding interference\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — commentary summarizing experimental findings; the mechanistic claim is attributed to a primary study referenced within, replicated across context\",\n      \"pmids\": [\"30287465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The ERFE-A260S variant leads to increased ERFE protein levels and impairs the BMP/SMAD pathway in hepatic cells, resulting in iron overload. Functional characterization in hepatic cell systems demonstrated that this variant acts as a modifier of iron regulation.\",\n      \"method\": \"Functional characterization of ERFE-A260S variant in hepatic cell systems, BMP/SMAD pathway analysis, patient cohort genotyping\",\n      \"journal\": \"American journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assay with pathway readout and patient genetic data, single lab, two complementary approaches\",\n      \"pmids\": [\"31400017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CTRP15 (ERFE) produced by cardiac myocytes inhibits TGF-β1-induced Smad3 activation and myofibroblast differentiation in cardiac fibroblasts. This anti-fibrotic effect is mediated through activation of the insulin receptor (IR)/IRS-1/Akt pathway, and blockade of IR/IRS-1/Akt reverses the inhibitory effect of CTRP15 on Smad3.\",\n      \"method\": \"AAV9-mediated overexpression in pressure-overloaded mice, recombinant CTRP15 treatment of cardiac fibroblasts, conditioned medium experiments, adenovirus/siRNA knockdown, Western blotting, immunofluorescence, pathway inhibitor rescue experiments\",\n      \"journal\": \"Cardiovascular drugs and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments with pathway inhibitor rescue establishing IR/IRS-1/Akt→Smad3 mechanism, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32424654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTRP15 (ERFE) promotes macrophage cholesterol efflux and attenuates atherosclerosis by upregulating ABCA1 expression via a T-cadherin/miR-101-3p/ABCA1 pathway: CTRP15 upregulates T-cadherin, which decreases miR-101-3p expression, thereby de-repressing ABCA1 and facilitating reverse cholesterol transport.\",\n      \"method\": \"Lentivirus-mediated CTRP15 overexpression in apoE-/- mice, in vitro macrophage cholesterol efflux assays, miRNA and gene expression analysis\",\n      \"journal\": \"Journal of physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments with pathway dissection, single lab, multiple complementary methods\",\n      \"pmids\": [\"35286626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERFE expression in spleen is regulated by the EPO/STAT5 signaling pathway. In metabolic syndrome rats, reduced EPO leads to downregulation of STAT5/ERFE signaling, and restoration by CIHH treatment upregulates this pathway, subsequently downregulating hepatic hepcidin via the BMP/SMAD pathway.\",\n      \"method\": \"In vivo rat model (metabolic syndrome with/without CIHH), protein expression analysis (JAK2, STAT3, STAT5, BMP6, SMAD1), mRNA quantification of ERFE and hepcidin\",\n      \"journal\": \"Journal of trace elements in medicine and biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo correlative signaling data without direct manipulation of ERFE, single lab, indirect pathway inference\",\n      \"pmids\": [\"37413927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Codon-optimized FAM132b (ERFE) with mutations A136T and P159A, delivered by AAV9, improved glucose intolerance and insulin resistance in high-fat diet mice. Structural analysis predicted the mutant may interact with β2 adrenergic receptor (ADRB2) and insulin/insulin-receptor complexes. FAM132b knockdown by shRNA increased glycemic response to epinephrine and reduced adipocyte response to epinephrine and adipose tissue browning.\",\n      \"method\": \"AAV9 gene delivery in high-fat diet mice, shRNA knockdown in vivo, structural biology prediction, in vivo metabolic phenotyping\",\n      \"journal\": \"International journal of obesity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo overexpression/KD with phenotype, receptor interaction is computational prediction only, single lab\",\n      \"pmids\": [\"35922561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL14-mediated m6A methylation of ERFE mRNA stabilizes ERFE through IGF2BP3-dependent reading of the m6A mark, thereby increasing ERFE levels. In cisplatin-treated renal tubular cells, this METTL14/IGF2BP3/ERFE axis promotes ferroptosis; METTL14 knockdown attenuates ferroptosis by downregulating ERFE, while IGF2BP3 overexpression reverses this effect and ERFE depletion abrogates the reversal.\",\n      \"method\": \"MeRIP-PCR (m6A detection on ERFE mRNA), RIP assay (IGF2BP3-ERFE mRNA binding), Actinomycin D mRNA stability assay, siRNA knockdown/overexpression in HK-2 cells, ferroptosis marker quantification\",\n      \"journal\": \"Journal of trace elements in medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct m6A mapping by MeRIP-PCR, RIP assay for reader binding, mRNA stability assay, epistasis rescue experiments, single lab\",\n      \"pmids\": [\"41205320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Osteocytes express ERFE (Fam132b) and upregulate it in response to EPO and hypoxia. Osteocyte-derived ERFE contributes to systemic hepcidin suppression during stress erythropoiesis: mice with ERFE-deficient osteocytes (bone marrow transplant model) show significantly less liver hepcidin suppression after phlebotomy. Mice lacking EPO receptors specifically in osteocytes (Epor-flox × Dmp1-Cre) also show reduced hepcidin suppression after phlebotomy.\",\n      \"method\": \"Bulk RNAseq of isolated osteocytes, bone marrow transplantation into Erfe-/- mice, conditional EPO receptor knockout in osteocytes (Epor-flox × Dmp1-Cre), phlebotomy stress model, liver hepcidin quantification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent genetic mouse models with defined cellular readout, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.09.27.615409\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ERFE (erythroferrone/myonectin/CTRP15/FAM132B) is a secreted C1q/TNF-family protein produced primarily by erythroid precursors and skeletal muscle (and also by osteocytes) that suppresses liver hepcidin expression by acting as an extracellular BMP ligand trap—directly binding specific BMP ligands to prevent their receptor engagement and downstream SMAD signaling—in an EPO/STAT5-regulated manner; it also promotes fatty acid uptake in liver and adipose tissue, exerts anti-fibrotic effects via IR/IRS-1/Akt→Smad3 signaling in cardiac fibroblasts, and promotes macrophage cholesterol efflux through a T-cadherin/miR-101-3p/ABCA1 axis, while its mRNA stability is post-transcriptionally regulated by METTL14-mediated m6A methylation read by IGF2BP3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ERFE (erythroferrone/myonectin/CTRP15/FAM132B) is a secreted C1q/TNF-family protein that couples erythropoietic and metabolic demand to systemic iron homeostasis by acting as an extracellular BMP pathway antagonist [#1, #2]. Its central iron-regulatory function is to suppress liver hepcidin: acting downstream of EPO, ERFE interferes with the engagement of specific BMP ligands by their receptors, blocking BMP/SMAD signaling in the liver [#2, #6], and this BMP-inhibitory activity is independent of the conserved C1q domain [#1]. ERFE is produced by multiple cell types under erythropoietic stress, including osteocytes, where EPO/EPOR signaling drives its expression and contributes to systemic hepcidin suppression after phlebotomy [#9]. The gain-of-function ERFE-A260S variant raises ERFE protein, impairs hepatic BMP/SMAD signaling, and causes iron overload, establishing ERFE as a modifier of human iron regulation [#3]. Beyond iron metabolism, ERFE has documented roles in lipid handling—promoting fatty acid uptake in adipocytes and hepatocytes via induction of CD36, FATP1, Fabp1, and Fabp4 [#0]—and its mRNA is stabilized post-transcriptionally by METTL14-deposited m6A marks read by IGF2BP3 [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Before its iron role was known, the protein was characterized as a muscle-secreted myokine, establishing it as a circulating C1q/TNF-family factor that influences peripheral lipid handling.\",\n      \"evidence\": \"Recombinant protein administration in mice plus in vitro fatty acid uptake assays in adipocytes/hepatocytes\",\n      \"pmids\": [\"22351773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or direct binding partner identified for the fatty-acid-uptake effect\", \"Link between lipid metabolism and later iron/BMP functions not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the iron-regulatory mechanism, showing ERFE acts downstream of EPO to suppress hepcidin by interfering with BMP ligand–receptor binding rather than acting as a conventional hormone on a dedicated receptor.\",\n      \"evidence\": \"Commentary summarizing experimental EPO→ERFE→BMP receptor interference data\",\n      \"pmids\": [\"30287465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the specific BMP ligands trapped not resolved here\", \"Source is a commentary, not the primary dataset\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established mechanistically that ERFE is an extracellular BMP antagonist acting by direct ligand binding, and mapped the activity to a region outside the conserved C1q domain.\",\n      \"evidence\": \"Gain-of-function and morpholino knockdown in Xenopus embryos, ectodermal explant assays, domain-deletion experiments, RNAseq\",\n      \"pmids\": [\"31846624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which BMP ligands are bound with what affinity not quantified\", \"Structural basis of ligand sequestration unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected ERFE function to human disease by showing a gain-of-function variant raises ERFE, impairs hepatic BMP/SMAD signaling, and drives iron overload.\",\n      \"evidence\": \"Functional characterization of ERFE-A260S in hepatic cells with BMP/SMAD readout plus patient cohort genotyping\",\n      \"pmids\": [\"31400017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which A260S elevates protein level unclear\", \"Penetrance and modifier interactions in patients not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended ERFE biology to the heart, identifying an anti-fibrotic action mediated through IR/IRS-1/Akt signaling that antagonizes TGF-β1/Smad3, distinct from its extracellular BMP-trap mechanism.\",\n      \"evidence\": \"AAV9 overexpression in pressure-overloaded mice, recombinant protein and conditioned-medium treatment of cardiac fibroblasts, pathway inhibitor rescue\",\n      \"pmids\": [\"32424654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ERFE–IR binding not demonstrated\", \"Reconciliation with BMP-trap mechanism unaddressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a vascular/metabolic role in which ERFE promotes macrophage cholesterol efflux through a T-cadherin/miR-101-3p/ABCA1 axis.\",\n      \"evidence\": \"Lentiviral CTRP15 overexpression in apoE-/- mice plus in vitro macrophage cholesterol efflux and miRNA/gene expression assays\",\n      \"pmids\": [\"35286626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction between ERFE and T-cadherin not shown biochemically\", \"Relevance to iron/BMP signaling unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated ERFE in glucose homeostasis, with overexpression improving insulin resistance and knockdown impairing adipose epinephrine response, though candidate receptors were only computationally predicted.\",\n      \"evidence\": \"AAV9 gene delivery and shRNA knockdown in high-fat-diet mice with metabolic phenotyping; structural prediction of ADRB2/insulin-receptor interaction\",\n      \"pmids\": [\"35922561\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Receptor interactions (ADRB2, insulin receptor) are in silico predictions only, not experimentally validated\", \"Mutant construct (A136T/P159A) confounds interpretation of native function\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided in vivo correlative support that EPO/STAT5 governs ERFE expression and that this axis tunes hepatic hepcidin via BMP/SMAD in a metabolic-disease context.\",\n      \"evidence\": \"Rat metabolic syndrome model with/without CIHH, protein and mRNA quantification of STAT5/ERFE/hepcidin/BMP-SMAD components\",\n      \"pmids\": [\"37413927\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct manipulation of ERFE; pathway linkage is correlative\", \"STAT5 control of ERFE shown by association, not genetic perturbation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified osteocytes as an additional EPO-responsive cellular source of ERFE that contributes to systemic hepcidin suppression during stress erythropoiesis.\",\n      \"evidence\": \"Osteocyte RNAseq, bone marrow transplant into Erfe-/- mice, osteocyte-specific Epor knockout (Dmp1-Cre), phlebotomy stress model with liver hepcidin readout (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.09.27.615409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of osteocyte vs erythroid ERFE not resolved\", \"Preprint, not yet peer-reviewed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed post-transcriptional control of ERFE, showing METTL14-deposited m6A marks read by IGF2BP3 stabilize ERFE mRNA, with functional consequences for renal tubular ferroptosis.\",\n      \"evidence\": \"MeRIP-PCR, IGF2BP3 RIP, actinomycin D mRNA stability assay, siRNA/overexpression and epistasis rescue in HK-2 cells\",\n      \"pmids\": [\"41205320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether m6A regulation operates in erythroid/osteocyte ERFE sources untested\", \"Mechanism linking ERFE level to ferroptosis not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the specific BMP ligands ERFE traps and a structural model of the ligand-binding interface remain undefined, as does how ERFE's multiple receptor-coupled effects (IR/IRS-1, T-cadherin, predicted ADRB2) relate to its extracellular BMP-antagonist mode.\",\n      \"evidence\": \"No timeline discovery resolves the ligand-binding structure or unifies the receptor-mediated mechanisms\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ERFE–BMP ligand complex\", \"No validated cell-surface receptor for the metabolic effects\", \"Tissue-specific selectivity among ERFE functions unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BMP6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}