Disorders of iron homeostasis, resulting in iron deficiency or overload, are very common worldwide (1). Normal iron homeostasis depends on a close link between dietary iron absorption and body iron needs (2). The paper by Nicolas et al. in this issue of PNAS (3) presents the exciting possibility that a central player in the communication of body iron stores to the intestinal absorptive cells may have been identified. This unlikely player, originally identified as a circulating antimicrobial peptide, is the hepatic protein hepcidin. Nicolas et al. found absence of hepcidin expression in mice exhibiting iron overload consequent to targeted disruption of the gene encoding the transcription factor Upstream Stimulatory Factor 2 (USF2).

A brief review of normal iron metabolism is useful in understanding the proposed role for hepcidin. Dietary free iron, on reduction from the ferric (Fe3+) to the ferrous (Fe2+) state on the luminal surface of the proximal small intestine (4), is transported into the enterocytes by the apical transporter DMT1 (also known as DCT1, Nramp2)(5). Dietary heme iron is taken up by an as-yetunidentified transporter and released from the heme molecule within the enterocyte. The iron may be stored within the enterocyte as ferritin (and lost with the senescent enterocyte) or transferred across the basolateral membrane to the plasma by the transport protein Ireg1 (6)[other names are ferroportin1 (7) and MTP1 (8)]. This latter process requires oxidation of Fe2+ to Fe3+ by hephaestin (9). Once iron has entered the circulation, there are no significant physiologic mechanisms for iron loss other than menstruation.