Erythropoietic regulators of iron metabolism

Erythropoiesis is the predominant consumer of iron in humans and other vertebrates. By decreasing the transcription of the gene encoding the iron-regulatory hormone hepcidin, erythropoietic activity stimulates iron absorption, as well as the release of iron from recycling macrophages and from stores in hepatocytes. The main erythroid regulator of hepcidin is erythroferrone (ERFE), synthesized and secreted by erythroblasts in the marrow and extramedullary sites. The production of ERFE is induced by erythropoietin (EPO) and is also proportional to the total number of responsive erythroblasts. ERFE acts on hepatocytes to suppress the production of hepcidin, through an as yet unknown mechanism that involves the bone morphogenetic protein pathway. By suppressing hepcidin, ERFE facilitates iron delivery during stress erythropoiesis but also contributes to iron overload in anemias with ineffective erythropoiesis. Although most of these mechanisms have been defined in mouse models, studies to date indicate that the pathophysiology of ERFE is similar in humans. ERFE antagonists and mimics may prove useful for the prevention and treatment of iron disorders. [Display omitted] •Systemic iron homeostasis is controlled by the peptide hormone hepcidin.•Hepcidin binds to iron exporter ferroportin to control iron efflux into plasma.•Systemic iron homeostasis is closely coupled to erythropoiesis.•Erythroferrone is a glycoprotein secreted by erythropoietin-primed erythroblasts.•Erythroferrone signals erythroid demand for iron by suppressing hepcidin production.