Cañeque Tatiana, Baron Leeroy, Müller Sebastian, Carmona Alanis, Colombeau Ludovic, Versini Antoine, Solier Stéphanie, Gaillet Christine, Sindikubwabo Fabien, Sampaio Julio L, Sabatier Marie, Mishima Eikan, Picard-Bernes Armel, Syx Laurène, Servant Nicolas, Lombard Bérangère, Loew Damarys, Zheng Jiashuo, Proneth Bettina, Thoidingjam Leishemba K, Grimaud Laurence, Fraser Cameron S, Szylo Krystina J, Der Kazarian Emma, Bonnet Caroline, Charafe-Jauffret Emmanuelle, Ginestier Christophe, Santofimia-Castaño 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 Florêncio Porto, Friedmann Angeli José Pedro, Stockwell Brent R, Conrad Marcus, Ubellacker Jessalyn M, Rodriguez Raphaël
Institut Curie, CNRS, INSERM, PSL Research University, Paris, France.
Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Nature. 2025 May 7. doi: 10.1038/s41586-025-08974-4.
Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis. 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 ferroptosis; by contrast, small molecules can provide spatiotemporal control of the chemistry at work. 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 CD44 primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation while conferring vulnerability to ferroptosis. 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 states.
铁催化生物膜中脂质的氧化，并促进一种称为铁死亡的细胞死亡形式。确定这种化学反应在细胞中的发生位置可以为设计能够在各种与疾病相关的情况下诱导或抑制铁死亡的药物提供依据。遗传学方法已经揭示了铁死亡的抑制因子；相比之下，小分子可以对正在起作用的化学反应提供时空控制。在这里，我们表明铁死亡抑制剂liproxstatin-1通过使溶酶体中的铁失活来发挥细胞保护作用。我们还表明，铁死亡诱导剂RSL3在溶酶体中引发膜脂质氧化。我们设计了一种溶酶体铁的小分子激活剂——芬托霉素-1，以诱导磷脂的氧化降解并最终导致铁死亡。芬托霉素-1能够杀死富含铁的CD44原发性肉瘤和胰腺导管腺癌细胞，这些细胞可以促进转移并增强药物耐受性。在这类细胞中，铁调节细胞适应性，同时使细胞对铁死亡敏感。暴露于亚致死剂量芬托霉素-1的肉瘤细胞获得一种铁死亡抗性细胞状态，其特征在于间充质标志物的下调和膜损伤反应的激活。这种磷脂降解剂可以在体外根除耐药物的持久性癌细胞，并在乳腺癌转移的小鼠模型中减少淋巴结内肿瘤生长。总之，这些结果表明控制铁的反应性具有治疗益处，将溶酶体铁确立为一个可成药靶点，并突出了靶向细胞状态的价值。
