Fig. 3: Graphic representation of the cellular mechanisms involved in the increase in ferroptotic events.

Ferroptosis leads to membrane destabilization, mitochondrial dysfunction, cytoskeletal rearrangements, and protein impairment. It is triggered by an imbalance between lipid hydroperoxide detoxification and iron-dependent ROS accumulation. The peroxidation of Polyunsaturated fatty acids (PUFAs) is limited by glutathione peroxidase 4 (GPX4), which utilizing glutathione (GSH), converts the lipid hydroperoxide in lipid alcohol. When equilibrium is lost, the oxidized lipid species (4-Hydroxynonenal and Malondialdehyde) accumulate in membranes, destabilizing them and leading to cell death. SLC7A11, solute carrier family 7 member 11 and SLC3A2, solute carrier family 3 member 2 allow the internalization of cystine need for GSH synthesis. A key ferroptotic player is glutathione depletion and/or the inactivation of glutathione-dependent antioxidant enzyme GPX4. Source of iron are heme and cytosolic ferritin degradation. Under conditions of iron restriction, NCOA4 binds to the H-subunit of ferritin, carrying it to lysosomes (ferritinophagy), where the protein is degraded and iron is released; during iron excess, NCOA4 is degraded by the ubiquitin–proteasome system, making cytosolic ferritin free to sequester iron.