Molecular mechanisms of hepcidin regulation. So far, three molecular pathways are found to be involved in the regulation of hepcidin, JAK/STAT3, BMP/SMAD and HFE/TfR2 pathways. Inflammatory stimuli, such as IL-6, induce hepcidin synthesis through the JAK/STAT3 pathway. Hepatic cellular iron can increase the expression of BMP-6. The released BMP6 then interacts with BMPR and HJV to form a complex and activates the SMAD pathway. The SMAD pathway involves phosphorylation of SMAD1, 5, and 8 (pSMADs), formation of pSMADs/SMAD4 complex, and the subsequent translocation of this complex to the nucleus to activate the expression of the hepcidin gene. Extracellular Tf-Fe2+ mediates a second iron signal. When the serum transferrin saturation increases, Tf-Fe2+ displaces HFE from TfR1. HFE then interacts with TfR2 to form the HFE/TfR2 complex. The HFE/TfR2 complex activates hepcidin transcription via HJV/BMP/SMAD and/or ERK/MAPK signaling pathway. Furthermore, HJV is subjected to cleavage by furin and TMPRSS6 to form a soluble HJV (sHJV), which can selectively inhibit BMP-induced hepcidin expression. Furin and TMPRSS6 can be regulated by hypoxia via HIF-1. Erythropoiesis may control hepcidin expression by EPO production. EPO subsequently stimulates GDF15 expression, which acts together with TWSG1 to inhibit hepatic hepcidin expression by inhibiting the BMP/SMAD pathway.