Liver iron transcriptionally activates BMP6, which recruits BMP receptors (BMPRs) and HJV for SMAD1/5/8 pathway activation. The SMAD complex translocates to the nucleus to bind the BMP Responsive Elements (BREs) in hepcidin promoter. Binding of HFE to TfR2 positively modulates hepcidin expression through a still unclear, likely SMAD-related, mechanism. TMPRSS6 inhibits hepcidin through the cleavage of HJV that reduces the BMP-SMAD pathway signaling. Ineffective erythropoiesis down-regulates hepcidin expression through activation of hepcidin inhibitors (iron deficiency and hypoxia and/or TMPRSS6, not shown). High hepcidin/low iron improves ineffective erythropoiesis, likely decreasing iron supply to single erythroid cells. Professional illustration by Marie Dauenheimer.