Mechanisms of hepcidin inhibition in iron deficiency anemia. Main cells/organs involved in hepcidin (HAMP) inhibition in iron deficiency are illustrated. In the hepatocytes, bone morphogenic protein (BMP)-SMAD signaling, the main activator of hepcidin, is low because low levels of BMP6 are produced by liver sinusoidal endothelial cells (L-SEC), the BMP coreceptor hemojuvelin (HJV) is cleaved from the hepatocyte surface by the transmembrane serine protease 6 (TMPRSS6), and the second transferrin receptor (TFR2) is not stabilized on the cell surface in the absence of the ligand diferric transferrin (TF). Low hepcidin levels increase iron absorption by enterocytes and recycling by macrophages through increased activity of the iron exporter FPN. In mild iron deficiency in the absence of hypoxia, increased EPO sensitivity is due to the loss of TFR2 on erythroblast surfaces. Histone deacetylase 3 (HIDAC3) participates in hepcidin suppression by erasing markers of activation at the hepcidin locus. In iron deficiency anemia, hypoxia increases EPO. Increased ERFE fully blocks the hepcidin pathway, although the molecular mechanism of hepcidin inhibition by ERFE remains unknown (?). BMPR, BMP receptor; CP, ceruloplasmin; DCYTB, duodenal cytochrome B; DMT1, divalent metal transporter 1; EPOR, EPO receptor; HEPH, hephestin.