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While lipid radical elimination reaction catalyzed by glutathione peroxidase 4 (GPX4) is a major anti-ferroptosis mechanism, inhibiting this pathway pharmaceutically shows promise as an antitumor strategy. However, certain tumor cells exhibit redundancy in lipid radical elimination pathways, rendering them unresponsive to GPX4 inhibitors. In this study, we conducted screens across different cancer cell lines and Food and Drug Administration-approved drugs, leading to the identification of temsirolimus in combination with the GPX4 inhibitor RSL3 as a potent inducer of ferroptosis in liver cancer cells. Mechanistically, temsirolimus sensitized liver cancer cells to ferroptosis by directly binding to and inhibiting ferroptosis suppressor protein 1 (FSP1) enzyme. Notably, while temsirolimus is recognized as a potent mammalian target of rapamycin (mTOR) inhibitor, its ferroptosis-inducing effect is primarily attributed to the inhibition of FSP1 rather than mTOR activity. By employing in vitro colony formation assays and in vivo tumor xenograft models, we demonstrated that the combination of temsirolimus and RSL3 effectively suppressed liver tumor progression. This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis. In conclusion, our findings underscore the potential of combining multitarget ferroptosis-inducing agents to circumvent the resistance to ferroptosis of liver cancer cells and highlight temsirolimus as a promising FSP1 inhibitor and ferroptosis inducer, which also deserves further investigation in translational medicine.<\/jats:p>","DOI":"10.1093\/jmcb\/mjae036","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T01:25:05Z","timestamp":1727141105000},"source":"Crossref","is-referenced-by-count":9,"title":["Temsirolimus inhibits FSP1 enzyme activity to induce ferroptosis and restrain liver cancer progression"],"prefix":"10.1093","volume":"16","author":[{"given":"Rui-Lin","family":"Tian","sequence":"first","affiliation":[{"name":"Huashan Hospital, Fudan University; Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University , Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5215-830X","authenticated-orcid":false,"given":"Tian-Xiang","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Westlake University, and Westlake Laboratory of Life Sciences and Biomedicine , Hangzhou 310024 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Xuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Huashan Hospital, Fudan University; Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University , Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Medical Research and Innovation of Pudong Hospital, and Intelligent Medicine Institute, Shanghai Medical College, Fudan University , Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Liang","family":"Guan","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Westlake University, and Westlake Laboratory of Life Sciences and Biomedicine , Hangzhou 310024 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xiong","sequence":"additional","affiliation":[{"name":"Cullgen Inc. , 12730 High Bluff Drive, San Diego, CA 92130 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9185-1913","authenticated-orcid":false,"given":"Pu","family":"Wang","sequence":"additional","affiliation":[{"name":"Huashan Hospital, Fudan University; Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University , Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Ye","sequence":"additional","affiliation":[{"name":"Huashan Hospital, Fudan University; Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University , Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"2025030501205251400_bib1","first-page":"808","article-title":"[Rapamycin and CCI-779]","volume":"86","author":"Alexandre","year":"1999","journal-title":"Bull. 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Thorac. Oncol."},{"key":"2025030501205251400_bib30","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/s41419-023-06042-1","article-title":"Irreversible HER2 inhibitors overcome resistance to the RSL3 ferroptosis inducer in non-HER2 amplified luminal breast cancer","volume":"14","author":"Park","year":"2023","journal-title":"Cell Death Dis."},{"key":"2025030501205251400_bib31","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1182\/blood.2022019274","article-title":"BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis","volume":"142","author":"Schmitt","year":"2023","journal-title":"Blood"},{"key":"2025030501205251400_bib32","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nchembio.2079","article-title":"Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis","volume":"12","author":"Shimada","year":"2016","journal-title":"Nat. Chem. 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