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. 2023 Aug 14;14(8):519. doi: 10.1038/s41419-023-06045-y

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — The GPX4-GSH pathway occurs mainly in the cytoplasm (cGPX4) and mitochondria (mGPX4). This axis can be inhibited by FINs and tumor suppressor p53. The FSP1-CoQ pathway occurs in the plasma membrane which can be inhibited by iFSP. The GCH1-BH4 pathway starts from the substrate GTP and inhibits lipid peroxidation by BH4–BH2 cycle. The DHODH-CoQH2 pathway is located at the outer surface of inner mitochondrial membrane, which catalyzes the conversion of DHO to OA while simultaneously refreshing CoQH2 to clear lipid radicals. SLC7A11 solute carrier family 7 member 11, cGPX4 cytoplasmic glutathione peroxidase 4, GSH glutathione, GSSG glutathione disulfide, PL-OO· Phospholipid hydroperoxide, FIN ferroptosis inducing, PULA long-chain polyunsaturated fatty acids, ACSL4: acyl-CoA synthetase long-chain family member 4, FSP1: ferroptosis suppressor protein 1; iFSP1 FSP1 small-molecule inhibitor, GCH1 cyclohydrolase-1, GTP cyclohydrolase-1, PTS 6-pyruvoyltetrahydropterin synthase, SPR sepiapterin reductase, DHFR dihydrofolate reductase, DHODH dihydroorotate dehydrogenase, OA orotate, DHO dihydroorotate, mGPX4 mitochondrial glutathione peroxidase 4.