Activation of lysosomal iron triggers ferroptosis in cancer

• 成果类型: Article
• 署名作者: Caneque, Tatiana; Baron, Leeroy; Mueller, Sebastian; Carmona, Alanis; Colombeau, Ludovic; Versini, Antoine; Solier, Stephanie; Gaillet, Christine; Sindikubwabo, Fabien; Sampaio, Julio L.; Sabatier, Marie; Mishima, Eikan; Picard-Bernes, Armel; Syx, Laurene; Servant, Nicolas; Lombard, Berangere; Loew, Damarys; Zheng, Jiashuo; Proneth, Bettina; Thoidingjam, Leishemba K.; Grimaud, Laurence; Fraser, Cameron S.; Szylo, Krystina J.; Kazarian, Emma Der; Bonnet, Caroline; Charafe-Jauffret, Emmanuelle; Ginestier, Christophe; Santofimia-Castano, Patricia; Estaras, Matias; Dusetti, Nelson; Iovanna, Juan Lucio; Cunha, Antonio Sa; Pittau, Gabriella; Hammel, Pascal; Tzanis, Dimitri; Bonvalot, Sylvie; Watson, Sarah; Gandon, Vincent; Upadhyay, Aditya; Pratt, Derek A.; Freitas, Florencio Porto; Angeli, Jose Pedro Friedmann; Stockwell, Brent R.; Conrad, Marcus; Ubellacker, Jessalyn M.; Rodriguez, Raphael
• 署名单位: Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Universite PSL; Institut Curie; Centre National de la Recherche Scientifique (CNRS); Harvard University; Harvard T.H. Chan School of Public Health; UNICANCER; Universite PSL; Institut Curie; Universite Paris Saclay; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; UNICANCER; Universite PSL; Institut Curie; MINES ParisTech; Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Universite PSL; Institut Curie; Centre National de la Recherche Scientifique (CNRS); Universite PSL; Ecole Normale Superieure (ENS); Aix-Marseille Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Institut Paoli-Calmette (IPC); Centre National de la Recherche Scientifique (CNRS); UNICANCER; Institut Paoli-Calmette (IPC); Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Aix-Marseille Universite; Universite Paris Saclay; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Paul-Brousse - APHP; UNICANCER; Universite PSL; Institut Curie; UNICANCER; Universite PSL; Institut Curie; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS); University of Ottawa; University of Wurzburg; Columbia University; Columbia University; Columbia University; Technical University of Munich
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1066
• DOI: 10.1038/s41586-025-08974-4
• 发表日期: 2025-06-12
• 关键词: lipid-peroxidation; cells; addiction; regulator; damage; dna

摘要

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis1. Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis2, 3-4; by contrast, small molecules can provide spatiotemporal control of the chemistry at work5. Here we show that the ferroptosis inhibitor liproxstatin-1 exerts cytoprotective effects by inactivating iron in lysosomes. We also show that the ferroptosis inducer RSL3 initiates membrane lipid oxidation in lysosomes. We designed a small-molecule activator of lysosomal iron-fentomycin-1-to induce the oxidative degradation of phospholipids and ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation6,7 while conferring vulnerability to ferroptosis8,9. Sarcoma cells exposed to sublethal doses of fentomycin-1 acquire a ferroptosis-resistant cell state characterized by the downregulation of mesenchymal markers and the activation of a membrane-damage response. This phospholipid degrader can eradicate drug-tolerant persister cancer cells in vitro and reduces intranodal tumour growth in a mouse model of breast cancer metastasis. Together, these results show that control of iron reactivity confers therapeutic benefits, establish lysosomal iron as a druggable target and highlight the value of targeting cell states10.