溶酶体铁的激活引发癌症中的铁死亡，这一成果由Raphaël Rodriguez课题组经过不懈努力而取得。这一研究成果发表在2025年5月7日出版的国际学术期刊《自然》上。

本研究表明，铁死亡抑制剂利普司他汀-1通过灭活溶酶体中的铁来发挥细胞保护作用。该研究组还表明，铁死亡诱导剂RSL3在溶酶体中启动膜脂氧化。该课题组人员设计了一种溶酶体铁-芬霉素-1的小分子激活剂来诱导磷脂的氧化降解，最终导致铁死亡。Fentomycin-1能够杀死富铁CD44高的原发性肉瘤和胰腺导管腺癌细胞，促进转移和促进药物耐受。在这些细胞中，铁调节细胞适应，同时赋予其对铁中毒的易感性。暴露于亚致死剂量芬太霉素-1的肉瘤细胞获得一种抗铁细胞状态，其特征是间充质标志物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持续性癌细胞，并在乳腺癌转移的单主题模型中减少结内肿瘤的生长。综上所述，这些结果表明控制铁反应性具有治疗益处，并确立了溶酶体铁作为一种可药物靶点，并强调了靶向细胞状态的价值。

研究人员表示，铁催化生物膜中的脂质氧化，并促进一种称为铁中毒的细胞死亡形式。确定这种化学反应在细胞中发生的位置，可以为设计能够在各种疾病相关环境中诱导或抑制铁死亡的药物提供信息。遗传方法已经揭示了铁凋亡的抑制因子；相比之下，小分子可以对起作用的化学物质进行时空控制。

附：英文原文

Title: Activation of lysosomal iron triggers ferroptosis in cancer

Author: Caeque, Tatiana, Baron, Leeroy, Mller, Sebastian, Carmona, Alanis, Colombeau, Ludovic, Versini, Antoine, Solier, Stphanie, Gaillet, Christine, Sindikubwabo, Fabien, Sampaio, Julio L., Sabatier, Marie, Mishima, Eikan, Picard-Bernes, Armel, Syx, Laurne, Servant, Nicolas, Lombard, Brangre, 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-Castao, 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, Florncio Porto, Friedmann Angeli, Jos Pedro, Stockwell, Brent R., Conrad, Marcus, Ubellacker, Jessalyn M., Rodriguez, Raphal

Issue&Volume: 2025-05-07

Abstract: 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.

DOI: 10.1038/s41586-025-08974-4

Source: https://www.nature.com/articles/s41586-025-08974-4