Systemic iron homeostasis regulation by hepcidin and ferroportin. Hepcidin and ferroportin control iron entry into the circulation from dietary sources and body stores to maintain systemic iron homeostasis. Iron deficiency and erythropoietic demand suppress hepcidin production by hepatocytes (left). In the absence of hepcidin, ferroportin is stabilized on the basolateral surface of duodenal enterocytes, iron-recycling macrophages, and hepatocytes, where it transports iron (Fe) from the intracellular space to the plasma for loading onto transferrin (TF) and delivery to red blood cells and other tissues. Iron loading and inflammation stimulate hepatocyte hepcidin production and secretion into the circulation, where it binds to ferroportin to cause its ubiquitination (U), endocytosis, and degradation (right). Hepcidin binding also interferes with ferroportin export activity independent of endocytosis. Hepcidin thereby limits iron overload and sequesters iron from invading pathogens.