FIGURE 3.
Iron metabolism and ferroptosis. Ferric state of iron (Fe3+) is bound to transferrin (Tf) in serum. Transferrin receptor 1 (TfR1) recognizes and binds the complex, which facilitates the endocytosis of ferric iron. The six-transmembrane epithelial antigen of the prostate-3 (Steap3) and acidic environment of the endosome jointly promote the reduction and release of ferrous iron (Fe2+). Divalent metal transporter 1 (DMT1) transports ferrous iron to cytoplasm, which is tightly controlled by ferritin. Autophagy (or ferritinophagy) selectively degrades ferritin with the coordination of nuclear receptor coactivator 4 (NCOA4), whose downregulation releases ferrous iron to activate lipid peroxidation, ultimately leading to ferroptosis. In addition, ferrous iron also triggers mitochondria-derived ROS through siderofexin (SFXN1). Ferroportin1 (FPN) can transport ferrous iron out of cell, which decreases the intracellular concentration of ferrous iron.