Abstract
Ferroptosis is an iron-dependent form of nonapoptotic cell death driven by lipid peroxidation. The selenium-dependent glutathione peroxidase 4 (GPX4) serves as the central regulator of ferroptosis through enzymatic reduction of phospholipid hydroperoxides (PLOOH). While GPX4 remains the canonical ferroptosis suppressor, whether alternative regulatory axes exist beyond this selenoprotein-mediated pathway remains unclear. In the present study, we identified selenomethionine as a novel resister of ferroptosis induced by RSL3 through screening FDA drug library and natural product library. Mechanistically, selenomethionine serves as a selenium donor for GPX4 biosynthesis beyond the transsulfuration pathway. The anti-ferroptosis activity of selenomethionine persists even after CRISPR-mediated GPX4 knockout, revealing a GPX4-independent mechanism that relies on direct redox modulation via selenium-mediated reactive oxygen species (ROS) scavenging. Significantly, selenomethionine administration effectively mitigated cisplatin-induced acute kidney injury in vivo by suppressing ferroptosis. This work establishes selenomethionine as a unique dual-mechanism ferroptosis suppressor that simultaneously modulates enzymatic antioxidant defense through GPX4 biosynthesis and non-enzymatic radical trapping via selenium-mediated redox cycling, providing new insights into therapeutic strategies for ferroptosis-related pathologies.
Similar content being viewed by others
References
Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185:2401–21.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.
Xia CY, Gao LC, Min JS, Fu CY. Mitochondria ATP pro-ferroptosis by adjusting the conversion of PUFA to PUFA-PLs. Medcomm-Oncol. 2025;4:e70038.
Sassano ML, Tyurina YY, Diokmetzidou A, Vervoort E, Tyurin VA, More S, et al. Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis. Nat Cell Biol. 2025;27:902–17.
Green DR. The coming decade of cell death research: five riddles. Cell. 2019;177:1094–107.
Newton K, Strasser A, Kayagaki N, Dixit VM. Cell death. Cell. 2024;187:235–56.
Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375:1254–61.
Co HKC, Wu CC, Lee YC, Chen SH. Emergence of large-scale cell death through ferroptotic trigger waves. Nature. 2024;631:654–62.
Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:266–82.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.
Conrad M, Pratt DA. The chemical basis of ferroptosis. Nat Chem Biol. 2019;15:1137–47.
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.
Yao Y, Chen Z, Zhang H, Chen C, Zeng M, Yunis J, et al. Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol. 2021;22:1127–39.
Mayr L, Grabherr F, Schwarzler J, Reitmeier I, Sommer F, Gehmacher T, et al. Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease. Nat Commun. 2020;11:1775.
Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91.
Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575:688–92.
Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575:693–8.
Tonnus W, Maremonti F, Gavali S, Schlecht MN, Gembardt F, Belavgeni A, et al. Multiple oestradiol functions inhibit ferroptosis and acute kidney injury. Nature. 2025;645:1011–9.
Kraft VAN, Bezjian CT, Pfeiffer S, Ringelstetter L, Muller C, Zandkarimi F, et al. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent Sci. 2020;6:41–53.
Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593:586–90.
Freitas FP, Alborzinia H, Dos Santos AF, Nepachalovich P, Pedrera L, Zilka O, et al. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Nature. 2024;626:401–10.
Li Y, Ran Q, Duan Q, Jin J, Wang Y, Yu L, et al. 7-Dehydrocholesterol dictates ferroptosis sensitivity. Nature. 2024;626:411–8.
Mishima E, Ito J, Wu Z, Nakamura T, Wahida A, Doll S, et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature. 2022;608:778–83.
Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochem Biophys Res Commun. 2017;482:419–25.
Labunskyy VM, Hatfield DL, Gladyshev VN. Selenoproteins: molecular pathways and physiological roles. Physiol Rev. 2014;94:739–77.
Chen Z, Inague A, Kaushal K, Fazeli G, Schilling D, Xavier da Silva TN, et al. PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance. Mol Cell. 2024;84:46–4559.e9.
Kang YP, Mockabee-Macias A, Jiang C, Falzone A, Prieto-Farigua N, Stone E, et al. Non-canonical glutamate-cysteine ligase activity protects against ferroptosis. Cell Metab. 2021;33:174–89.e7.
Cao J, Chen X, Jiang L, Lu B, Yuan M, Zhu D, et al. DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase. Nat Commun. 2020;11:1251.
Xia C, Xing X, Zhang W, Wang Y, Jin X, Wang Y, et al. Cysteine and homocysteine can be exploited by GPX4 in ferroptosis inhibition independent of GSH synthesis. Redox Biol. 2024;69:102999.
Xia C, Peng P, Zhang W, Xing X, Jin X, Du J, et al. Methionine-SAM metabolism-dependent ubiquinone synthesis is crucial for ROS accumulation in ferroptosis induction. Nat Commun. 2024;15:8971.
Lin Q, Li S, Jin H, Cai H, Zhu X, Yang Y, et al. Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis. Int J Biol Sci. 2023;19:1192–210.
Deng Y, Zeng L, Liu H, Zuo A, Zhou J, Yang Y, et al. Silibinin attenuates ferroptosis in acute kidney injury by targeting FTH1. Redox Biol. 2024;77:103360.
Fujita H, Tanaka YK, Ogata S, Suzuki N, Kuno S, Barayeu U, et al. PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis. Nat Struct Mol Biol. 2024;31:1277–85.
Okuno T, Ueno H, Nakamuro K. Cystathionine gamma-lyase contributes to selenomethionine detoxification and cytosolic glutathione peroxidase biosynthesis in mouse liver. Biol Trace Elem Res. 2006;109:155–71.
Lee N, Park SJ, Lange M, Tseyang T, Doshi MB, Kim TY, et al. Selenium reduction of ubiquinone via SQOR suppresses ferroptosis. Nat Metab. 2024;6:343–58.
Le DT, Liang X, Fomenko DE, Raza AS, Chong CK, Carlson BA, et al. Analysis of methionine/selenomethionine oxidation and methionine sulfoxide reductase function using methionine-rich proteins and antibodies against their oxidized forms. Biochemistry. 2008;47:6685–94.
Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and Transferrin Regulate Ferroptosis. Mol Cell. 2015;59:298–308.
Acknowledgements
This work was supported by the Zhejiang Provincial Natural and Science Foundation of China under Grant (LD22H310004), Zhejiang Provincial Natural and Science Foundation (LQN25C070001), Zhejiang Sci-Tech University Research Start-up Fund (24042191-Y).
Author information
Authors and Affiliations
Contributions
C.X. conceived the idea, designed the experiments, and composed the paper. C.X., X.S., and J.S. conducted experiments; C.W., S.M., and F.Z. assisted in animal experiments; J.S. assisted in qPCR; C.W. assisted in CRISPR/Cas9-mediated gene knockout; C.X., C.F., and Q.Z. supervised the project.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Edited by Professor Boyi Gan
Rights and permissions
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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Xia, C., Sun, X., Shao, J. et al. Selenomethionine as a dual-mechanism ferroptosis inhibitor: selenium-supply-driven GPX4 biosynthesis beyond transsulfuration and reductive-capacity-mediated ROS scavenging independent of GPX4 activity. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08466-x
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41419-026-08466-x
