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. Author manuscript; available in PMC: 2021 May 24.
Published in final edited form as: Nat Rev Mol Cell Biol. 2021 Jan 25;22(4):266–282. doi: 10.1038/s41580-020-00324-8

Figure 2. Ferroptosis-suppressing pathways.

Figure 2.

(A) The canonical ferroptosis controlling axis entails uptake of cystine via the cystine-glutamate antiporter, designated system xc−, glutathione (GSH)- and/or thioredoxin reductase 1 (TXNRD1)-dependent reduction of cystine to cysteine, GSH biosynthesis, and glutathione peroxidase 4 (GPX4)-mediated reduction of phospholipid hydroperoxides (PL-OOH) yielding the corresponding alcohols (P-LOH). Recycling of oxidized glutathione (GSSG) is achieved via glutathione-disulfide reductase (GSR) using electrons provided by NADPH/H+. (B) In two independent genetics screens the FSP1/ubiquinone (CoQ10) system has been recently identified that completely protects against ferroptosis induced by pharmacological inhibition or genetic deletion of GPX4. FSP1 prevents lipid peroxidation and associated ferroptosis via reduction of ubiquinol/α-tocopherol on the level of lipid radicals unlike GPX4/GSH. (C) Alternate ferroptosis-suppressive mechanisms include squalene- and di-/tetrahydrobiopterin (BH2/BH4)-mediated inhibition of lipid peroxidation, although the chemical mechanisms how this is achieved remains to be shown (Abbreviations: ACSL4, acyl-CoA synthetase long chain family member 4; FDFT1, Farnesyl-diphosphate farnesyltransferase 1; GCH1, GTP cyclohydrolase 1, LOX, lipoxygenase; LPCAT3 lysophosphatidylcholine acyltransferase 3, POR, cytochrome P450 oxidoreductase, PUFA, polyunsaturated fatty acid).