Regulation of hepcidin by iron. Binding of BMP6 to receptors (BMPRs) at the hepatocyte plasma membrane results in phosphorylation (P) of receptor-associated SMAD proteins (R-SMADs), which form a complex with the common mediator SMAD4. This SMAD4 complex translocates to the nucleus to bind specific regulatory elements in the promoter of the hepcidin gene, increasing hepcidin transcription. The glycosylphosphatidylinositol-linked protein HJV acts as a BMP coreceptor that promotes hepcidin signaling through this pathway. Neogenin may interact with HJV and enhance BMP signaling. In contrast, the transmembrane serine protease TMPRSS6 inhibits hepcidin signaling through the BMP pathway by cleaving HJV from the plasma membrane. Hepatic BMP6 production increases in response to chronic iron loading, suggesting an autocrine or paracrine mechanism for regulating hepcidin synthesis to limit the progression of systemic iron loading. Binding of holo-transferrin (HoloTf) to TFR1 displaces HFE, which may interact with TFR2 to promote hepcidin expression. Whereas evidence suggests that HFE modulates hepcidin signaling through the BMP pathway, how HFE and its interactions with TFR1 and TFR2 may relate functionally to the BMP pathway is not yet known.