Hepcidin regulation by iron. Increase in transferrin saturation induces hepcidin transcription via the BMP/SMAD signaling pathway. Diferric transferrin binds to TfR2, while BMP6 and BMP2 secreted by liver sinusoidal endothelial cells (LSECs) bind to BMP receptors on hepatocytes. These events trigger phosphorylation of regulatory SMAD1/5/8, recruitment of SMAD4, and translocation of the SMAD complex to the nucleus for activating hepcidin transcription upon binding to BMP/SMAD responsive element in the HAMP promoter. BMPs can be trapped by ERFE, leading to hepcidin inhibition in iron-loading anemias. Efficient iron signaling requires the BMP coreceptor HJV and the protein HFE, and is negatively regulated by the transmembrane serine protease matriptase-2 (TMPRSS6). The complex molecular pathogenesis of HC reflects the numerous proteins involved in the regulation of the hepcidin-ferroportin axis.