What Is Erythroferrone? Definition and What Research Reports

Definition

Erythroferrone (ERFE) is a secreted protein hormone produced chiefly by developing red blood cell precursors (erythroblasts) in the bone marrow and spleen after they are stimulated by erythropoietin. Reviews of iron biology describe erythroferrone as the messenger that connects the demand for new red blood cells to the release of iron, because it acts on the liver to suppress production of hepcidin, the master regulator of iron export from cells (PMID 39027903). When hepcidin falls, more iron reaches the plasma from intestinal absorption and from storage in macrophages and hepatocytes, which is the supply route for haemoglobin synthesis (PMID 28387022). The term is used in the literature both for the molecule itself and, increasingly, as a measurable biomarker of erythropoietic drive.

What Class of Molecule It Is

Erythroferrone is a full-length secreted glycoprotein rather than a short synthetic peptide. It belongs to the C1q/TNF-related protein (CTRP) family and appears in the literature under several names: FAM132B, CTRP15 and myonectin, the last reflecting its identification in skeletal muscle before its erythroid role was characterised. Because it circulates, acts at a distant organ (the liver) and is regulated by another hormone (erythropoietin), reviews classify it functionally as a hormone within the broader group of protein and peptide signalling molecules studied in iron and erythropoiesis research (PMID 37639548).

Where It Comes From

• Primary source: erythroblasts in bone marrow and, in stress erythropoiesis, the spleen, following erythropoietin receptor signalling (PMID 35628152).
• Trigger: conditions that raise erythropoietin — bleeding, hypoxia, haemolysis and ineffective erythropoiesis — increase erythroferrone transcription in reviews of iron homeostasis (PMID 28387022).
• Target: hepatocytes, where reviews report that erythroferrone interferes with bone morphogenetic protein signalling that would otherwise drive hepcidin transcription (PMID 39027903).
• Other tissue: the same molecule has been studied under the name myonectin in skeletal muscle contexts (PMID 38052214).

How the Term Is Used in Research

In published work, "erythroferrone" usually appears in one of three ways. First, as a mechanistic node in the erythropoietin–erythroferrone–hepcidin–ferroportin axis described in reviews of how iron supply is matched to red cell production (PMID 37639548). Second, as a circulating biomarker measured alongside erythropoietin, hepcidin, ferritin and soluble transferrin receptor to gauge how much erythropoietic drive a patient has. Third, as an experimental variable in animal models, where its gene is deleted, over-expressed or pharmacologically bypassed to test causation. Researchers also study upstream and parallel components, such as transferrin receptor 2, whose murine expression was examined in relation to erythropoietin exposure (PMID 34360974).

Common contexts in the literature

What the Published Literature Reports

Reviews of systemic iron handling reported that erythropoietin-driven erythroferrone release lowers hepcidin, and that this mechanism explains why iron absorption and iron release from stores rise when erythropoiesis is expanded (PMID 28387022). A dedicated 2024 review of erythroferrone in iron metabolism and haematopathologies summarised its discovery, its regulation and its proposed roles across anaemias and iron-loading disorders (PMID 39027903). A separate review framed erythroferrone within the wider "iron mining" problem of how erythroblasts obtain enough iron for haemoglobin (PMID 35628152).

In disease states marked by ineffective erythropoiesis, the pattern reported is chronic erythroferrone excess with inappropriately low hepcidin and progressive iron loading. A review of congenital dyserythropoietic anaemias described this combination of ineffective erythropoiesis and iron overload as a defining feature of the group (PMID 32702750). A paediatric study comparing transfusion-dependent and non-transfusion-dependent thalassemias measured erythropoiesis and iron parameters across the two groups and reported differences between them (PMID 34157011). Consistent with the same axis, researchers reported that ineffective erythropoiesis was corrected and iron homeostasis normalised in transfusion-dependent β-thalassemia after treatment with exagamglogene autotemcel (PMID 42252696), and that mitapivat improved ineffective erythropoiesis and iron overload in adults with pyruvate kinase deficiency (PMID 38330179).

The opposite scenario — too little erythroferrone signalling relative to need — has been probed experimentally. In an adenine-induced mouse model of chronic kidney disease, the study reported that transgenic augmentation of erythroferrone ameliorated anaemia (PMID 40773297). In humans, a clinical study of dapagliflozin reported suppression of hepcidin together with increased erythropoiesis, linking a metabolic drug to the same regulatory pathway (PMID 32044999). Outside erythropoiesis, researchers reported that FK506 bypassed the effect of erythroferrone on skeletal muscle atrophy in cancer cachexia models, indicating the molecule has actions beyond the liver (PMID 38052214).

Erythroferrone Research and Safety: What Studies Report

Erythroferrone is not a marketed medicine and is not administered to people as a therapy in the literature cited here, so there is no adverse-event profile for it as a product. What the cited work reports instead are the consequences attributed to endogenous erythroferrone activity. Reviews of ineffective erythropoiesis described sustained hepcidin suppression as a contributor to iron overload in disorders such as congenital dyserythropoietic anaemia (PMID 32702750) and thalassemia (PMID 34157011). In the cachexia setting, the study reported erythroferrone as a mediator whose effect on skeletal muscle atrophy could be bypassed pharmacologically (PMID 38052214). Whether interventions that raise or lower erythroferrone are safe in humans has not been established by the papers listed here; the mouse over-expression work remains preclinical (PMID 40773297).

Terms often confused with erythroferrone

• Erythropoietin (EPO): the kidney-derived hormone upstream of erythroferrone that drives erythroblast production (PMID 37639548).
• Hepcidin: the liver peptide hormone downstream of erythroferrone that controls iron export (PMID 28387022).
• Ferroportin: the cellular iron exporter that hepcidin acts on (PMID 35628152).
• Transferrin receptor 2: a separate iron-sensing component whose murine expression was studied in relation to erythropoietin (PMID 34360974).

Bottom Line

Erythroferrone is best understood as an erythroid-derived hormone that tells the liver to stand down hepcidin production so that iron can be mobilised for haemoglobin synthesis. Most of the published work treats it as a mechanism and a biomarker rather than a treatment: measured in anaemias with ineffective erythropoiesis, tracked as disease-modifying therapies normalise iron handling (PMID 42252696), and manipulated in animal models to test causation (PMID 40773297). This page is for educational purposes only and is not medical advice; consult a licensed physician about any medical condition, laboratory result or treatment decision.

References

• Erythroferrone in focus: emerging perspectives in iron metabolism and hematopathologies (Blood Science, 2024)
• Systemic iron homeostasis and erythropoiesis (IUBMB Life, 2017)
• Iron Mining for Erythropoiesis (International Journal of Molecular Sciences, 2022)
• Regulation of erythropoiesis: emerging concepts and therapeutic implications (Hematology, 2023)
• Congenital dyserythropoietic anemias (Blood, 2020)
• Erythropoiesis and Iron Parameters in Transfusion-dependent and Nontransfusion-dependent Thalassemias (Journal of Pediatric Hematology/Oncology, 2021)
• Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency (Blood Advances, 2024)
• Correction of Ineffective Erythropoiesis and Normalization of Iron Homeostasis After Exagamglogene Autotemcel in Transfusion-Dependent β-Thalassemia (American Journal of Hematology, 2026)
• Transgenic augmentation of erythroferrone in mice ameliorates anemia in adenine-induced chronic kidney disease (JCI Insight, 2025)
• Dapagliflozin Suppresses Hepcidin And Increases Erythropoiesis (Journal of Clinical Endocrinology and Metabolism, 2020)
• Effect of Erythropoietin on the Expression of Murine Transferrin Receptor 2 (International Journal of Molecular Sciences, 2021)
• FK506 bypasses the effect of erythroferrone in cancer cachexia skeletal muscle atrophy (Cell Reports Medicine, 2023)