Article Dans Une Revue Nature Année : 2025

Activation of lysosomal iron triggers ferroptosis in cancer

Tatiana Cañeque
Leeroy Baron
Sebastian Müller
Ludovic Colombeau
Antoine Versini
Christine Gaillet
Fabien Sindikubwabo
Julio L Sampaio
Marie Sabatier
Bérangère Lombard
Damarys Loew
Leishemba K Thoidingjam
Cameron S Fraser
Krystina J Szylo
Antonio Sa Cunha
Gabriella Pittau
Pascal Hammel
Dimitri Tzanis
Sylvie Bonvalot
Sarah Watson
Brent R Stockwell
Jessalyn M Ubellacker

Résumé

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.

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Dates et versions

hal-05237505 , version 1 (24-09-2025)

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Tatiana Cañeque, Leeroy Baron, Sebastian Müller, Alanis Carmona, Ludovic Colombeau, et al.. Activation of lysosomal iron triggers ferroptosis in cancer. Nature, 2025, 642 (8067), pp.492-500. ⟨10.1038/s41586-025-08974-4⟩. ⟨hal-05237505⟩
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