Erythroferrone: An Erythroid Regulator of Hepcidin and Iron Metabolism

Iron homeostasis ensures adequate iron for biological processes while preventing excessive iron accumulation, which can lead to tissue injury. In mammalian systems, iron availability is controlled by the interaction of the iron-regulatory hormone hepcidin with ferroportin, a molecule that functions both as the hepcidin receptor as well as the sole known cellular exporter of iron. By reducing iron export through ferroportin to blood plasma, hepcidin inhibits the mobilization of iron from stores and the absorption of dietary iron. Among the many processes requiring iron, erythropoiesis is the most iron-intensive, consuming most iron circulating in blood plasma. Under conditions of enhanced erythropoiesis, more iron is required to provide developing erythroblasts with adequate iron for heme and hemoglobin synthesis. Here the hormone erythroferrone, produced by erythroblasts, acts on hepatocytes to suppress hepcidin production, and thereby increase dietary iron absorption and mobilization from stores. This review focuses on the discovery of erythroferrone and recent advances in understanding the role of this hormone in the regulation of iron homeostasis during states of increased erythropoietic demand. Gaps in our understanding of the role of erythroferrone are highlighted for future study.