Progress in iron metabolism research.

Abstract

Iron is essential for various cellular processes, but an excess of iron may cause organ damage through the production of reactive oxygen species. Therefore, the amount of iron in the body must be strictly controlled. The central regulator of systemic iron homeostasis is hepcidin, which is primarily produced in the liver. Various molecules, including HFE, transferrin receptor 2 (TFR2), and hemojuvelin (HJV), are involved in sensing systemic iron status. Hepatocytes produce hepcidin in response to excess iron and inflammatory stimuli (e.g., interleukin-6), whereas hepcidin expression is downregulated by hypoxia, anemia, and erythropoietic activity. In mice, erythroferrone, secreted from erythroblasts, suppresses hepcidin expression. Hepcidin downregulates the protein expression of ferroportin, the only iron exporter in mammalian cells, and thereby downregulates iron absorption from intestine and iron release from macrophages. Mutations in the genes HFE, TFR2, HJV, HAMP (encoding hepcidin), and SLC40A1 (encoding ferroportin) cause hereditary hemochromatosis, whereas mutations in TMPRSS6 (which encodes matriptase 2) cause iron-refractory iron deficiency anemia through the upregulation of hepcidin expression. In chronic anemias, such as β-thalassemia, myelodysplastic syndromes, and aplastic anemia, repeated red blood cell transfusion can cause systemic iron overload. Iron chelation therapy improves the prognosis of patients with such conditions.