How does EPO suppress hepcidin expression? Shown is a model of EPO-mediated hepcidin suppression. In conditions of iron excess, BMP6 is abundantly expressed and stimulates hepcidin expression by the liver in a pathway dependent on the BMP co-receptor HJV. Hepcidin inhibits dietary iron absorption and release of macrophage iron stores, thereby restoring iron to physiologic levels. In states of EPO excess such as anemia, EPO suppresses hepcidin expression in a pathway dependent upon matriptase-2; ERFE, a recently identified erythroid regulator, also suppresses hepcidin expression but its functional relationship to matriptase-2 and other components of this pathway has yet to be elucidated. For simplicity, many factors of relevance to erythropoiesis, hepcidin regulation, and iron metabolism have been omitted. Green arrows indicate stimulation or activation; red lines indicate inhibition. Professional illustration by Patrick Lane, ScEYEnce Studios.