FIGURE 2.

Mechanisms of ferroptosis regulation. The classic GPX4 (glutathione peroxidase 4) pathway. System Xc-brings cystine into cells and is reduced to cystine under the action of GSH, and cystine is an important synthetic raw material for GSH. GPX4 reduces PL-OOH (phospholipid hydroperoxide) to PL-OH in the presence of GSH, thereby inhibiting ferroptosis. ACSL4 (acyl-CoA synthetase long chain family member 4)/LPCAT3 (lysophosphatidylcholine acyltransferase 3) is a very important driver of ferroptosis. PUFA (polyunsaturated fatty acid) is catalyzed by ACSL4 to generate PUFA-CoA, which is then catalyzed by LPCAT3 to generate PL (phospholipid), which is finally catalyzed by LOXs (lipoxygenase) to generate PL-OOH, and then lipid peroxidation occurs, eventually leading to The membrane ruptures, driving iron death. 2. The accumulation of a large amount of iron ions in cells can also induce ferroptosis. 3. P53-mediated ferroptosis pathway. One of the pathways is to inhibit the expression of SLC7A11 (solute carrier family 7 member 11) in the System Xc-complex, thereby inhibiting GSH synthesis, resulting in the inhibition of GPX4 activity and ultimately the induction of ferroptosis. In addition, decreased expression of SLC7A11 increases free ALox12 (lipoxygenase12), which catalyzes the production of PUFAs-OOH from PUFAs. Another pathway is to inhibit the activity of ALox12 through the downstream target gene iPLA2β of p53, thereby inhibiting the occurrence of ferroptosis. This also shows that P53 plays an important role in the process of ferroptosis.