FIGURE 1.

Overview of molecular and proteins, which are involved in ferroptosis, localized at the peroxisome membrane in mammals. Ferroptosis can be regulated by peroxisome synthesized ether-linked phospholipid and PPARs. G3P would be imported into peroxisomal membrane, then dehydronated by G3PDH and introduce DHAP. Then, DHAP acyltransferase (DHAPAT) uses fatty acyl CoA to acylate dihydroxyacetone phosphate (A-DHAP). Besides, fatty acyl CoA can be reduced to fatty alcohol by a peroxisomal membrane-associated fatty acyl CoA reductase with NADPH. Subsequently, acyl-DHAP is converted to alkyl-DHAP by peroxisomal fatty alcohol. Acyl- or alkyl-DHAP reductase (ADHAP) can reduce acyl-DHAP and alkyl-DHAP to 1-acyl-G3P and 1-O-alkyl-G3P, respectively. 1-acyl-G3P and 1-O-alkyl-G3P are imported into ER, and converted to diacylphospholipid or ether-linked phospholipids (ether-PL). Ether-PL can be oxidized to ether-PL-OOH, which has been considered a trigger of ferroptosis. PPARs have three receptor sub-types (PPARα, γ, and δ). PPARα and γ could facilitate MUFA synthesis to suppress ferroptosis. Although PPARδ has been reported to up-regulate the expression of ACSL3 to promote the synthesis of MUFA, PPARδ could also up-regulate ACSL4 which is a promoter of ferroptosis. PPAR, peroxisome proliferator-activated receptors; G3P, glycerol 3-phosphate; G3PDH, glycerol 3-phosphate dehydrogenase; DHAP, dihydroxyacetone phosphate; DHAPAT, DHAP acyltransferase; A-DHAP, acyl-DHAP; ADHAPR, acyl-/alkyl-DHAP reductase; PL, phospholipid; MUFA, monounsaturated fatty acids; ACSL, acyl-CoA synthetase long-chain family member; GSR, glutathione-disulfide reductase.