Systemic regulation of iron metabolism and utilization. Iron is either absorbed in the duodenum or recycled from senescent RBCs, and it is found in circulation bound to transferrin (diferric transferrin complex). Diferric transferrin delivers iron to the bone marrow for Hb synthesis in erythroid precursors. Erythropoiesis also requires the presence of erythropoietin (Epo) to enable erythroblast differentiation and enucleation. Epo-stimulated erythroblasts secrete erythroferrone (ERFE), which functions by sequestering bone morphogenic protein 6 (BMP6) in circulation and decreasing signaling to and suppression of hepcidin. Hepcidin functions in multiple ways to decrease circulating iron, including blocking release of iron from splenic macrophages and preventing iron absorption in the gut. This interrelated process is intended to prevent shortfalls and excess of systemic iron and fine tune iron transport to where it is needed. FPN1, ferroportin 1. Fe, iron; Tf, transferrin.