Figure 2.

Iron and ferritinophagy are required for ferroptosis induction. Iron release in the cytosol can generate Reactive Oxygen Species (ROS) by the Fenton Reaction. ROS leads to lipid peroxidation and ferroptosis. Iron increase in the cytosol is mediated by increased import (by the transferrin receptor: TfR), decreased export (by ferroportin), increased translation of iron-metabolism related mRNAs via Iron Response Element Binding Protein 2 (IREB2) and increased cytosolic flux by Divalent Metal Transporter 1 (DMT1). Iron can also be stored in ferritin and delivered to the lysosome for NCOA4-mediated iron release from the lysosome. Increased ferritinophagy flux contributes to ferroptosis. Glutathione Peroxidase 4 (GPx4) repairs lipid peroxidation and inhibits ferroptosis. Ferroptosis is a promising therapeutic target. Inhibiting ferroptosis could protect from iron-induced cell death in neurodegeneration and ischemia/reperfusion injury while triggering ferroptosis could be effective in cancer patients.