Activation of lysosomal iron triggers ferroptosis in cancer

Tatiana Cañeque, Leeroy Baron, Sebastian Müller, Alanis Carmona, Ludovic Colombeau, Antoine Versini, Stéphanie Solier, Christine Gaillet, Fabien Sindikubwabo, Julio L. Sampaio, Marie Sabatier, Eikan Mishima, Armel Picard-Bernes, Laurène Syx, Nicolas Servant, Bérangère Lombard, Damarys Loew, Jiashuo Zheng, Bettina Proneth, Leishemba K. Thoidingjam, Laurence Grimaud, Cameron S. Fraser, Krystina J. Szylo, Emma Kazarian, Caroline Bonnet, Emmanuelle Charafe-Jauffret, Christophe Ginestier, Patricia Santofimia-Castaño, Matias Estaras, Nelson Dusetti, Juan Lucio Iovanna, Antonio Sa Cunha, Gabriella Pittau, Pascal Hammel, Dimitri Tzanis, Sylvie Bonvalot, Sarah Watson, Vincent Gandon, Aditya Upadhyay, Derek A. Pratt, Florêncio Porto Freitas, José Pedro Friedmann Angeli, Brent R. Stockwell, Marcus Conrad, Jessalyn M. Ubellacker and Raphaël Rodriguez ()
Additional contact information
Tatiana Cañeque: PSL Research University
Leeroy Baron: PSL Research University
Sebastian Müller: PSL Research University
Alanis Carmona: Harvard T. H. Chan School of Public Health
Ludovic Colombeau: PSL Research University
Antoine Versini: PSL Research University
Stéphanie Solier: PSL Research University
Christine Gaillet: PSL Research University
Fabien Sindikubwabo: PSL Research University
Julio L. Sampaio: PSL Research University
Marie Sabatier: Harvard T. H. Chan School of Public Health
Eikan Mishima: Helmholtz Zentrum München
Armel Picard-Bernes: PSL Research University
Laurène Syx: PSL Research University
Nicolas Servant: PSL Research University
Bérangère Lombard: PSL Research University
Damarys Loew: PSL Research University
Jiashuo Zheng: Helmholtz Zentrum München
Bettina Proneth: Helmholtz Zentrum München
Leishemba K. Thoidingjam: PSL Research University
Laurence Grimaud: PSL Research University
Cameron S. Fraser: Harvard T. H. Chan School of Public Health
Krystina J. Szylo: Harvard T. H. Chan School of Public Health
Emma Kazarian: Aix-Marseille University
Caroline Bonnet: Aix-Marseille University
Emmanuelle Charafe-Jauffret: Aix-Marseille University
Christophe Ginestier: Aix-Marseille University
Patricia Santofimia-Castaño: Parc Scientifique et Technologique de Luminy
Matias Estaras: Parc Scientifique et Technologique de Luminy
Nelson Dusetti: Parc Scientifique et Technologique de Luminy
Juan Lucio Iovanna: Parc Scientifique et Technologique de Luminy
Antonio Sa Cunha: Paris Saclay University and Paul-Brousse Hospital (APHP Sud)
Gabriella Pittau: Paris Saclay University and Paul-Brousse Hospital (APHP Sud)
Pascal Hammel: Paris Saclay University and Paul-Brousse Hospital (APHP Sud)
Dimitri Tzanis: Institut Curie
Sylvie Bonvalot: Institut Curie
Sarah Watson: PSL Research University
Vincent Gandon: Paris Saclay University
Aditya Upadhyay: University of Ottawa
Derek A. Pratt: University of Ottawa
Florêncio Porto Freitas: Julius-Maximilians-Universität Würzburg
José Pedro Friedmann Angeli: Julius-Maximilians-Universität Würzburg
Brent R. Stockwell: Columbia University
Marcus Conrad: Helmholtz Zentrum München
Jessalyn M. Ubellacker: Harvard T. H. Chan School of Public Health
Raphaël Rodriguez: PSL Research University

Nature, 2025, vol. 642, issue 8067, 492-500

Abstract: 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 ferroptosis2–4; 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.

Date: 2025
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DOI: 10.1038/s41586-025-08974-4

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