Systemic iron regulation according to iron status. Shown is the differential regulation of liver hepcidin in conditions of iron overload (left) and iron deficiency (right). DMT1 in duodenal enterocytes takes up iron from the lumen after DCYTB reduces ferric to ferrous iron. At the basolateral membrane, iron is exported by FPN and oxidized by hephaestin. Iron-loaded transferrin (Tf-Fe2) delivers iron to cells by binding TFR1. After phagocytosis of RBCs by macrophages, heme released from hemoglobin is processed by heme oxygenase-1 (HOX1) to generate iron, which is then delivered to plasma through FPN. In iron overload (left), the high concentration of hepcidin binds and degrades FPN, blocking iron export. BMP6, stimulated by intracellular iron, increases hepcidin transcription in the liver. In iron deficiency (right), iron is released by FPN into the circulation. Production of hepcidin is low because of low BMP6 expression and because of inhibitory signals generated by iron-deficient erythropoiesis. Used with permission from Hentze et al.¹