ERFE

ERFE (erythroferrone) is a secreted BMP antagonist that suppresses hepatic hepcidin expression by directly binding BMP ligands in the extracellular space and preventing their engagement with BMP receptors, thereby de-repressing iron absorption and mobilization (PMID:31846624, PMID:30287465). ERFE is produced by erythroblasts (and osteocytes) downstream of EPO/STAT5 signaling, establishing a hormonal link between erythropoietic drive and iron supply (PMID:37413927, PMID:30287465). The BMP-inhibitory activity resides outside the conserved C1q domain, and a missense variant (A260S) that elevates ERFE levels acts as a genetic modifier of iron overload severity in congenital dyserythropoietic anemia type II (PMID:31846624, PMID:31400017).

1. 2018 Medium

   Establishing the epistatic position of ERFE between EPO signaling and BMP-receptor-mediated hepcidin induction resolved how erythropoietic demand communicates with the hepatic iron-sensing pathway.

   Evidence Synthesis of epistasis experiments (EPO→ERFE→BMP receptor binding interference→hepcidin suppression) referencing primary work by Arezes et al.

   PMID:30287465

   Open questions at the time

   • Direct binding between ERFE and specific BMP ligands not yet demonstrated at this stage
   • Structural basis for ERFE–BMP interaction unknown
2. 2019 High

   Demonstrating that ERFE directly interferes with BMP ligand–receptor binding at the extracellular level — and that the C1q domain is dispensable — established the molecular mechanism of hepcidin suppression and narrowed the active region of ERFE.

   Evidence Gain-of-function screen and ectodermal explant assays in Xenopus embryos; ERFE morpholino knockdown; domain deletion constructs

   PMID:30287465 PMID:31846624

   Open questions at the time

   • Identity of the minimal BMP-binding domain within ERFE not defined
   • No structural model of ERFE–BMP complex
   • Selectivity for individual BMP ligands (BMP2/6/etc.) not quantified biochemically
3. 2019 Medium

   Identification of the ERFE-A260S variant as a functional modifier of BMP/SMAD signaling linked ERFE genetic variation to clinical iron overload in congenital dyserythropoietic anemia type II.

   Evidence Functional characterization of A260S variant in hepatic cells using BMP/SMAD reporter assays and Western blot; genotype–phenotype correlation in patients

   PMID:31400017

   Open questions at the time

   • Mechanism by which A260S increases ERFE protein levels not determined
   • Replication in independent patient cohorts not reported
   • Effect size relative to other iron-overload modifiers not compared
4. 2023 Medium

   In vivo confirmation that EPO/STAT5 signaling induces ERFE, which in turn suppresses BMP/SMAD-dependent hepcidin in the liver, validated the EPO→STAT5→ERFE→BMP/SMAD→hepcidin axis in a mammalian physiological context.

   Evidence Metabolic syndrome rat model with chronic intermittent hypobaric hypoxia; Western blot for JAK2, STAT3, STAT5, BMP6, SMAD1, hepcidin; mRNA analysis

   PMID:37413927

   Open questions at the time

   • Single disease model (metabolic syndrome); generalizability to other erythropoietic stress states not tested
   • STAT5 direct binding to ERFE promoter not shown in this study
5. 2025 Medium

   Discovery that METTL14-mediated m6A modification stabilizes ERFE mRNA via IGF2BP3 revealed an epitranscriptomic layer of ERFE regulation and an unexpected role for ERFE in promoting ferroptosis in renal tubular cells.

   Evidence MeRIP-PCR, RIP assay for METTL14/IGF2BP3–ERFE mRNA binding, actinomycin D stability assay, siRNA knockdown with ferroptosis marker measurement in cisplatin-treated renal epithelial cells

   PMID:41205320

   Open questions at the time

   • Single cell type and injury model (cisplatin nephrotoxicity); relevance to erythropoietic tissues unknown
   • Whether m6A regulation of ERFE operates during physiological stress erythropoiesis not tested
   • Downstream mechanism by which ERFE promotes ferroptosis not elucidated

• The structural basis for ERFE–BMP ligand selectivity, the minimal active domain of ERFE, and the physiological contribution of non-erythroblast ERFE sources (e.g., osteocytes) to systemic iron homeostasis remain unresolved.
• No crystal or cryo-EM structure of ERFE or ERFE–BMP complex
• Quantitative contribution of osteocyte-derived versus erythroblast-derived ERFE to hepcidin regulation in vivo not established in peer-reviewed literature
• Whether ERFE-mediated ferroptosis in kidney has pathological relevance beyond cisplatin injury is unknown