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Previous studies have reported that inorganic and organic mercury compounds can induce apoptosis and necrosis in a variety of cell types, but more recent advances reveal that mercuric mercury (Hg2+) and methylmercury (CH3Hg+) may result in ferroptosis, a distinct form of programmed cell death. However, it is still unclear which protein targets are responsible for ferroptosis induced by Hg2+ and CH3Hg+. In this study, human embryonic kidney 293T cells were used to investigate how Hg2+ and CH3Hg+ trigger ferroptosis, given their nephrotoxicity. Our results demonstrate that glutathione peroxidase 4 (GPx4) plays a key role in lipid peroxidation and ferroptosis in renal cells induced by Hg2+ and CH3Hg+. The expression of GPx4, the only lipid repair enzyme in mammal cells, was downregulated in response to Hg2+ and CH3Hg+ stress. More importantly, the activity of GPx4 could be markedly inhibited by CH3Hg+, owing to the direct binding of the selenol group (\u2013SeH) in GPx4 to CH3Hg+. Selenite supplementation was demonstrated to enhance the expression and activity of GPx4 in renal cells, and consequently relieve the cytotoxicity of CH3Hg+, suggesting that GPx4 is a crucial modulator implicated in the Hg\u2013Se antagonism. These findings highlight the importance of GPx4 in mercury-induced ferroptosis, and provide an alternative explanation for how Hg2+ and CH3Hg+ induce cell death.<\/jats:p>","DOI":"10.1093\/mtomcs\/mfad014","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T14:31:53Z","timestamp":1677681113000},"source":"Crossref","is-referenced-by-count":20,"title":["Roles of glutathione peroxidase 4 on the mercury-triggered ferroptosis in renal cells: implications for the antagonism between selenium and mercury"],"prefix":"10.1093","volume":"15","author":[{"given":"Jiahao","family":"Chen","sequence":"first","affiliation":[{"name":"School of Environment, Hangzhou Institute for Advanced Study, UCAS , Hangzhou 310024, China"},{"name":"State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China"},{"name":"University of Chinese Academy of Sciences , Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghao","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China"},{"name":"University of Chinese Academy of Sciences , Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixia","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China"},{"name":"University of Chinese Academy of Sciences , Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China"},{"name":"University of Chinese Academy of Sciences , Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6213-4720","authenticated-orcid":false,"given":"Ligang","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Environment, Hangzhou Institute for Advanced Study, UCAS , Hangzhou 310024, China"},{"name":"State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China"},{"name":"University of Chinese Academy of Sciences , Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijin","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China"},{"name":"University of Chinese Academy of Sciences , Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4499-6116","authenticated-orcid":false,"given":"Ming","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Environment, Hangzhou Institute for Advanced Study, UCAS , Hangzhou 310024, China"},{"name":"State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China"},{"name":"University of Chinese Academy of Sciences , Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,3]]},"reference":[{"issue":"20","key":"2024012010405090100_bib1","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1016\/j.atmosenv.2009.06.009","article-title":"Global emission of mercury to the atmosphere from anthropogenic sources in 2005 and projections to 2020","volume":"44","author":"Pacyna","year":"2010","journal-title":"Atmos. 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