Regulation of hepcidin and iron availability. A, Hepcidin regulates systemic iron availability and enteral iron absorption by internalizing and degrading intracellular iron exporter ferroportin (FPN). An increase in hepcidin leads to reduced FPN levels that prevent enteral iron (Fe) from duodenal enterocytes, stored iron from hepatocytes, and recycled iron from senescent red blood cells (RBCs) in macrophages from export to the systemic circulation, which leads to iron restriction and functional iron deficiency. B, In cases of inflammation, interleukin (IL)-6 and IL-22 bind to their receptors that activate JAK2 and lead to phosphorylation of STAT3. Phosphorylated STAT3 then translocates to the cell nucleus and upregulates hepcidin by inducing transcription of the HAMP gene. In addition, other cytokines such as IL-1β, oxidative stress, endoplasmic reticulum (ER) stress, and infectious inflammation upregulate hepcidin by inducing transcription factors such as the CREBH or C/EBPα. C, In cases of iron overload, bone morphogenetic protein 6 (BMP6) binds to the BMP receptor (BMP-R) and coreceptor hemojuvelin (HJV). This leads to the phosphorylation of SMAD1/5/8, which binds with SMAD4 and translocates to the cell nucleus inducing HAMP transcription. It has been shown that the transferrin receptor 2 (TFR2) complex with human hemochromatosis protein (HFE) is important in the BMP-SMAD signaling activation. In cases of iron excess, ferritin bound to its transport protein transferrin (Tf-Fe) binds to TFR1, which leads to HFE dissociation from TFR1 and binding to TFR2. D, Iron deficiency, hypoxia, and increased erythropoiesis can downregulate hepcidin through multiple but not completely understood pathways. Under normoxic conditions, prolyl hydroxylases (PHDs) inhibit hypoxia-inducible transcription factors (HIFs). During hypoxia, HIFs upregulate protease matriptase 2 (MT2) that inhibits BMP-SMAD signaling and downregulates hepcidin. Hypoxia can also directly downregulate HAMP transcription. In cases of increased erythropoiesis, erythropoietin (EPO) upregulates erythroferrone (ERFE), which is known to inhibit BMP-SMAD signaling. Other potential erythroid regulators, such as growth and differentiation factor 15 (GDF15), might also downregulate hepcidin.