Figure 1.

The mechanisms and signaling pathways regulate the metabolisms of glutathione/GPX4, iron, and lipid in ferroptosis. The hallmarks of ferroptosis include the loss of lipid peroxide repair capacity by the phospholipid hydroperoxidase GPX4, the availability of redox-active iron, and oxidation of PUFA-containing phospholipids, which are regulated by the following signaling pathways. 1. Glutathione/GPX4 signaling pathways. The synthesis of tripeptide GSH protects cells from ferroptotic death, in that GSH is essential: (i) for the maintenance of the level of GPX4 through the exchange of glutamate and cystine via cystine/glutamate antiporter system Xc-, and (ii) for the functional activity of GPX4 to reduce lipid hydroperoxides (L-OOH) to lipid alcohols (L-OH), resulting in the prevention of the iron (Fe²⁺)-dependent formation of toxic lipid ROS. The inhibition of system Xc- or inhibition of GSH synthesis should result in lipid peroxides accumulation and ferroptotic cell death through inactivating GPX4. In addition, the mevalonate pathway, sulfur transfer pathway, glutamine pathway, and p53 signaling axis are also involved in the regulation of GPX4 activity and function. 2. Iron metabolic signaling pathway. Iron metabolism includes iron uptake (transferrin receptor), iron export (ferroportin), iron storing (ferritin), and ferritinophagy mediated by lysosome and NCOA4. Abnormal iron metabolism could induce iron overload resulting in lipid ROS production via the Fenton reaction. In addition, ferritin can be regulated by the ATG5-ATG7 and NCOA4 pathways as well as and IREB2. Furthermore, iron metabolism can be regulated by p62-Keap1-NRF2 and HSPB1 signaling pathways. 3. Lipid metabolic signaling pathway. Ferroptosis can be caused by an abnormal accumulation of lipid peroxidation, which is the archetype free radical chain reaction formally resulting in the insertion of O₂ into a C-H bond in the oxidizable free PUFAs. PUFAs can be transformed into PUFA-PEs by two enzymes, including ACSL4 for synthesizing PEs and LPCAT3 for lipid remodeling. PUFAs can also be oxidized to phospholipid hydroperoxides by LOXs. In addition, recent studies show that VDACs and the FSP1-CoQ10-NAD(P)H pathways exist as an independent parallel system that works cooperatively with GPX4/glutathione to regulate lipid peroxidation and ferroptosis. GSH: glutathione; TFR1: transferrin receptor 1; Fpn: ferroportin; NCOA4: nuclear receptor coactivator 4; DMT1: divalent metal transporter 1; ATG5: autophagy protein 5; ATG7: autophagy-related protein 7; IREB2: iron-responsive element-binding protein 2; HO-1: heme oxygenase 1; Nrf2: nuclear factor-erythroid factor 2-related factor 2; LIP: labile iron pool; PUFAs: polyunsaturated fatty acids; ACSL4: acyl-CoA synthetase long-chain family member 4; LPCAT3: lysophosphatidylcholine acyltransferase 3; PEs: phosphatidylethanolamines; LOXs: lipoxygenases; ALOX15: arachidonate lipoxygenase 15; VDACs: voltage-dependent anion channels.