The work of Wang et al is consistent with the following scenario. In the hepatocyte, SMAD1 and SMAD5 cooperate to mediate iron-related signaling through hemojuvelin (HJV), BMP, and BMP receptor (BMPR) for the promotion of hepcidin transcription through phosphorylated SMAD4. Homozygous inactivation of HJV or other molecules in the hepcidin-activation pathway leads to hemochromatosis through decreased SMAD1 and SMAD5 signaling and lack of hepcidin. Stimulation of erythroblasts by erythropoietin (EPO), especially in the setting of ineffective erythropoiesis, leads to increased production of erythroferrone by erythroblasts. In turn, erythroferrone serves to decrease phosphorylation (P) of SMAD1 and SMAD5 in hepatocytes, leading to iron loading as a result of lack of hepcidin.