Activation of lysosomal iron triggers ferroptosis in cancer

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis<sup>1</sup>. 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<sup>2-4</sup>; by contrast, small molecules can provide spatiotemporal control of the chemistry at work<sup>5</sup>. 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<sup>high</sup> primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation<sup>6,7</sup> while conferring vulnerability to ferroptosis<sup>8,9</sup>. 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<sup>10</sup>.

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Journal
Nature
Published
2025-05-07
DOI
https://doi.org/10.1038/s41586-025-08974-4
Citations
120
Primary Topic
Ferroptosis and cancer prognosis
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article
Field-Weighted Citation Impact
182.20
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article

Activation of lysosomal iron triggers ferroptosis in cancer

Nelson Dusetti, Raphaël Rodriguez, Damarys Loew, Dimitri Tzanis et al.
120 citations
Nature
Ferroptosis and cancer prognosis
182.20
article

Activation of lysosomal iron triggers ferroptosis in cancer

Nelson Dusetti, Raphaël Rodriguez, Damarys Loew, Dimitri Tzanis, Jessalyn M. Ubellacker, Leishemba K. Thoidingjam, Emmanuelle Charafe‐Jauffret, Bérangère Lombard, Patricia Santofimia‐Castaño, Stéphanie Solier, Tatiana Cañeque, Matías Estarás, Brent R. Stockwell, Antoine Versini, Christophe Ginestier, Derek A. Pratt, Marcus Conrad, Jiashuo Zheng, Gabriella Pittau, Júlio L. Sampaio, Sarah Watson, Bettina Proneth, Laurence Grimaud, Fabien Sindikubwabo, Alanis Carmona, Laurène Syx, Nicolas Servant, Sebastian Müller, Vincent Gandon, Sylvie Bonvalot, Christine Gaillet, Ludovic Colombeau, José Pedro Friedmann Angeli, Juan Iovanna, Pascal Hammel, António Sá Cunha, Eikan Mishima, Marie Sabatier, Florêncio Porto Freitas, Krystina J. Szylo, Leeroy Baron, Cameron Fraser, Armel Picard–Bernes, Caroline Bonnet, Aditya Upadhyay, Emma Der Kazarian
article en
120 citations

Abstract

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis<sup>1</sup>. 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<sup>2-4</sup>; by contrast, small molecules can provide spatiotemporal control of the chemistry at work<sup>5</sup>. 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<sup>high</sup> primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation<sup>6,7</sup> while conferring vulnerability to ferroptosis<sup>8,9</sup>. 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<sup>10</sup>.

NatureVol. 642(8067)
Centre National de la Recherche Scientifique (FR), Harvard University (US), University of Ottawa (CA), Inserm (FR), Université de Versailles Saint-Quentin-en-Yvelines (FR), Aix-Marseille Université (FR), University of Würzburg (DE), Université Paris Sciences et Lettres (FR), Université Paris-Saclay (FR), Harvard University Press (US), Institut Pprime (FR), Helmholtz Zentrum München (DE), La Ligue Contre le Cancer (FR), Assistance Publique – Hôpitaux de Paris (FR), École Normale Supérieure (BI), Génomique Bioinformatique et Applications (FR), Chimie et Biologie des Membranes et des Nanoobjects (FR), Centre de Recherche en Cancérologie de Marseille (FR), Institut Paoli-Calmettes (FR), Institut de Chimie Moléculaire et des Matériaux d'Orsay (FR), Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (FR), Hôpital Paul-Brousse (FR), Laboratoire des Biomolécules (FR), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie des systèmes complexes, Technical University of Munich (DE), Columbia University (US), Institut Curie (FR)
Openalex Percentile: Top 0%
Ferroptosis and cancer prognosis
182.20
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