Fig. 1: Fatty acid biosynthesis and ferroptosis.

Arachidonic acid (AA, C20:4) is an n-6 polyunsaturated fatty acid that can be synthesized from linoleic acid (C18:2) by fatty acid desaturases (FADSs) and elongation of very long-chain fatty acid proteins (ELOVLs) or taken up directly from the environment. AA and its elongation product, adrenic acid (AdA), are incorporated into membrane phospholipids via acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3). PE-AA and PE-AdA are considered the most vulnerable phospholipids to peroxidation, which may be mediated by lipoxygenases or via nonenzymatic autoxidation reactions. Peroxidation is followed by the generation of lipid radicals, such as the phospholipid peroxyl radical (PLOO∙), which contributes to the lipid peroxidation chain reaction and, ultimately, to ferroptosis. Ferroptosis can be prevented by reducing lipid hydroperoxides to lipid alcohols via glutathione peroxidase 4 (GPX4) or by directly halting lipid radicals via ferroptosis suppressor protein (FSP1)/CoQ₁₀/vitamin K (VK). The de novo lipogenesis (DNL) pathway contributes to the pool of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Although nonessential polyunsaturated fatty acids (PUFAs), such as n-7 and n-9 PUFAs, can be synthesized by FADS2 (Δ6 desaturase), mammals cannot synthesize essential PUFAs, such as n-3 and n-6 fatty acids, because they lack of Δ12 and Δ15 desaturases. Nonetheless, through the DNL pathway, SFAs, and MUFAs contribute to the abundance of n-6 PUFAs, positively or negatively impacting ferroptosis. Abbreviations: ACC acetyl-CoA carboxylase, AMPK AMP-activated protein kinase, FASN fatty acid synthase, GSH glutathione, GSSG glutathione disulfide, SCD1 stearoyl-CoA desaturase-1.