The mechanism of gastrointestinal tumors involved in the ferroptosis pathway (IMAGE)
Caption
① Antioxidant pathway: Cysteine is imported into cells to synthesize GSH through the SLC7A11/SLC3A2 complex. GPX4 uses GSH as a substrate to reduce membrane phospholipid hydroperoxides to harmless lipid alcohols, thereby preventing the accumulation of lethal lipid ROS and inhibiting ferroptosis. ② Lipid peroxidation pathway: ACSL4 catalyzes the connection of long-chain polyunsaturated fatty acids to coenzyme A, and LPCAT3 promotes esterification and the incorporation of these products into membrane phospholipids (PL). PUFA-containing PL is oxidized by the iron-dependent enzymes LOX or POR, leading to lipid peroxidation, membrane damage, and subsequent ferroptosis. ③ Overexpression of nuclear receptor coactivator 4 increases intracellular LIP by increasing ferritin degradation. The increased intracellular LIP can generate free radicals (hydroxyl radicals) through the Fenton reaction and participate in the peroxidation reaction of phospholipids to generate PLOOH. Most intracellular production of reactive oxygen species is iron-catalyzed. The production of ROS triggers lipid peroxidation and ultimately leads to ferroptosis. ACSL4, acyl-CoA synthetase long chain family member 4; CoA, coenzyme A; GPX4, glutathione peroxidase 4; GSH, glutathione; GSR, glutathione-disulfide reductase; GSSG, glutathione oxidized; LIP, labile iron pool; LOX, lipoxygenase; PL, phospholipid; PLOH, phospholipid alcohol; PLOOH, phospholipid hydroperoxide; POR, cytochrome P450 oxidoreductase; PUFA, polyunsaturated fatty acid; ROS, reactive oxygen species; xCT, cystine/glutamate antiporter.
Credit
Mingxin Zhang, Xin Quan
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