Fig. 6
Ferroptosis molecular machinery. Ferroptosis is an iron-dependent cell death which is executed by lipid peroxidation. The loss of iron regulation and functioning lipid peroxide repair systems foster lipid radical production and lipid peroxidation. 1- Iron dysregulation: During ferroptosis, there is an increase in the labile iron pool (LIP), which is the redox active iron. Within cells, the LIP increases through importing more iron through the upregulated divalent metal transporter 1 (DMT1) and transferrin receptors-1 (TFR1), limiting iron exportation by degrading FPN1, and releasing iron from its ferritin stores by the nuclear receptor co-activator 4 (NCOA4)- mediated ferritinophagy or ferritin degradation. At a molecular level, iron regulatory proteins (IRP1/2) are upregulated and bind to the iron responsive element (IRE) in the mRNA of iron-related proteins, increasing the the expression of TfR1 and DMT1 and inhibiting that of FPN1 and ferritin, which favors the build-up of LIP. 2-Loss of antioxidant defense: Through a Fenton-like reaction, ferrous iron (Fe+2), in the expanding LIP, acts on hydrogen peroxides (H2O2) to form highly reactive hydroxyl (OH●) radicals. The accumulation of reactive oxygen species (ROS) overwhelms the already-inflicted antioxidant defence system. During ferroptosis, nuclear factor erythroid 2-related factor 2 (NrF2) decrease and P53 increase can downregulate of the Solute carrier family 7 member 11 (SLC7A11), which denies the entry of cystine and therefore decrease the formation of glutathione (GSH). 3- Lipid peroxidation: During ferroptosis, an increase in acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) incorporates more polyunsaturated fatty acids (PUFA) into membrane phospholipid by binding them to coenzyme A to produce PUFA-CoAs. The abundance of ROS initiates a chain reaction of lipid peroxidation forming lipid hydroperoxides (PUFAOOH●). The chain reaction is amplified by the grown LIP and lipoxygenases (LOX) that help the enzymatic formation of PUFAOOH●. With the decreased availability of glutathione peroxidase 4 (GPX4) and GSH. The chain reaction of lipid peroxidation propagates extensively, inciting more and more ferroptosis