On the Inhibition of Lipid Peroxidation and Ferroptosis by Fatty Acids

Abstract Most inhibitors of lipid peroxidation (LPO) and associated ferroptosis are small molecules that trap LPO-propagating radicals. Among the handful of other inhibitors are select fatty acids: monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids substituted with deuterium atoms at their reactive bis-allylic positions (D-PUFAs), which render them significantly less reactive to LPO-propagating radicals. To probe whether the simple replacement of oxidizable PUFAs with non-oxidizable FAs is a general strategy for ferroptosis suppression, we prepared derivatives of representative PUFAs—linoleic acid (LA) and arachidonic acid (AA)—with cyclopropane rings in place of their unsaturations (CP-PUFAs). Cyclopropanation was predicted to boost the strength of the neighboring C−H bonds by ∼20 kcal/mol and increase the barrier to reaction with peroxyl radicals by ∼104-fold while preserving their cis geometry. CP-PUFAs suppressed ferroptosis induced by erastin2 in HT-1080 cells and RSL3 in HEK-293 cells, similarly to D-PUFAs and MUFAs. Palmitate, a representative endogenous saturated FA, did not suppress ferroptosis. Whereas d6-AA was more effective than d2-LA, the opposite was true of the CP-PUFAs, with CP4-AA possessing only modest activity while CP2-LA was comparable to the D-PUFAs. Lipidomics provides evidence for more extensive lipid remodeling upon treatment with CP2-LA relative to CP4-AA, with PUFAs being enriched in triacylglycerols at the expense of the diacylglycerols used for phospholipid synthesis. Overall, these results suggest that replacement of oxidizable PUFAs with non-oxidizable FAs is a general strategy to suppress ferroptosis—provided that the non-oxidizable FA can be utilized by the biosynthetic machinery and is not lipotoxic at concentrations necessary for protection.