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We found that iNKT cells, compared with CD4+ T cells, have significantly higher levels of lipid peroxidation in both mice and humans. Proteomic analysis also demonstrated that iNKT cells express higher levels of phospholipid hydroperoxidase glutathione peroxidase 4 (Gpx4), a major antioxidant enzyme that reduces lipid peroxidation and prevents ferroptosis. T cell\u2013specific deletion of Gpx4 reduces iNKT cell population, most prominently the IFN-\u03b3\u2013producing NKT1 subset. RNA-sequencing analysis revealed that IFN-\u03b3 signaling, cell cycle regulation, and mitochondrial function are perturbed by Gpx4 deletion in iNKT cells. Consistently, we detected impaired cytokine production, elevated cell proliferation and cell death, and accumulation of lipid peroxides and mitochondrial reactive oxygen species in Gpx4 knockout iNKT cells. Ferroptosis inhibitors, iron chelators, vitamin E, and vitamin K2 can prevent ferroptosis induced by Gpx4 deficiency in iNKT cells and ameliorate the impaired function of iNKT cells due to Gpx4 inhibition. Last, vitamin E rescues iNKT cell population in Gpx4 knockout mice. Altogether, our findings reveal the critical role of Gpx4 in regulating iNKT cell homeostasis and function, through controlling lipid peroxidation and ferroptosis.<\/jats:p>","DOI":"10.4049\/jimmunol.2400246","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T08:53:12Z","timestamp":1724057592000},"page":"941-951","source":"Crossref","is-referenced-by-count":19,"title":["Gpx4 Regulates Invariant NKT Cell Homeostasis and Function by Preventing Lipid Peroxidation and Ferroptosis"],"prefix":"10.1093","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5084-068X","authenticated-orcid":false,"given":"Sophia P M","family":"Sok","sequence":"first","affiliation":[{"name":"Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn","family":"Pipkin","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4809-9885","authenticated-orcid":false,"given":"Narcis I","family":"Popescu","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6841-5353","authenticated-orcid":false,"given":"Megan","family":"Reidy","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2734-6418","authenticated-orcid":false,"given":"Bin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, School of Medicine, University of California\u2013San Diego , La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0883-0642","authenticated-orcid":false,"given":"Holly","family":"Van Remmen","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation , Oklahoma City, OK"},{"name":"Oklahoma City Veterans Affairs Medical Center , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Kinter","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0572-2662","authenticated-orcid":false,"given":"Xiao-Hong","family":"Sun","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, UConn Health , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6392-4954","authenticated-orcid":false,"given":"Meng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation , Oklahoma City, OK"},{"name":"Department of Microbiology and Immunology, University of Oklahoma Health Science Center , Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"key":"2025012305164754100_r1","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1146\/annurev.immunol.23.021704.115742","article-title":"Toward an understanding of NKT cell biology: progress and paradoxes","volume":"23","author":"Kronenberg","year":"2005","journal-title":"Annu. 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