Fig. 1: Systemic iron sources and metabolism.

Dietary iron consists of Fe³⁺ and heme iron. Fe³⁺ is reduced to Fe²⁺ by DCYTB and then transported to intestinal cells by DMT1, whereas heme iron is transported to intestinal cells by HCP-1 and degraded by HO1 to produce Fe²⁺ in intestinal cells. Ferrous iron is released into capillaries via FPN (a unique iron exporter), where it binds to transferrin (TF) through oxidation of HEPN or CP. Finally, iron participates in the iron cycle through the TF-TFR1 pathway or SLC39A14-mediated NTBI. Macrophages degrade aged red blood cells to recycle iron, which represents another important source of iron for the body. EPO released by the kidney activates the HIF signaling pathway to promote erythrocyte production. The liver also plays an important role in iron regulation. TF and hepcidin are secreted by the liver to regulate iron homeostasis and used by the liver and other tissues. In addition to hepcidin, RNF217 maintains iron homeostasis by promoting the degradation of FPN. CP ceruloplasmin, DCYTB duodenal cytochrome b, DMT1 divalent metal transporter 1, EPO erythropoietin, FPN ferroportin, HCP-1 heme carrier protein 1, HEPH hephaestin, HIF hypoxia induced factor, HO1 heme oxygenase 1, NTBI non-transferrin-bound iron, RBCs red blood cells, TBI transferrin-bound iron, TFR1 transferrin receptor 1.