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. 2022 Jan 21;298(3):101617. doi: 10.1016/j.jbc.2022.101617

Figure 1.

Figure 1

The first and well-characterized pathway governing ferroptosis. Ferroptosis is mediated by an iron-dependent accumulation and propagation of lipid peroxidation reactions. Iron (Fe3+) bound to transferrin is internalized into cells via receptor-mediated endocytosis and subsequently released as redox-reactive iron (Fe2+) required for Fenton chemistry. Upstream ferroptosis induction can occur as a result of cysteine starvation via inhibition of system xC− using small-molecule inhibitors (Erastin, IKE, Glutamate), genetic deletion of SLC7A11, or cystine withdrawal, which result in diminished GSH levels, and impaired GPX4 activity. In addition, direct inhibition of GPX4 with small-molecule compounds ((1S,3R)-RSL3, ML162) or GPX4 depleting class of ferroptosis compounds, can impair antioxidant system and result in the accumulation of lipid ROS leading to ferroptosis. Accordingly, ferroptosis is blocked by iron chelators, DFO and CPX, as well as radical trapping antioxidants, Ferrostatin-1, Liproxstatin-1, and Vitamin E. CPX, ciclopirox; DFO, deferoxamine; GPX4, glutathione peroxidase 4; GSH, glutathione; IKE, imidazole ketone erastin; ML162, molecular libraries 162; PUFA-PLs, polyunsaturated fatty acid phospholipids; ROS, reactive oxygen species; RSL3, Ras selective lethal 3.