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Cited by 287Ferroptosis and cancer prognosisIron Metabolism and DisordersCell death mechanisms and regulation

Activation of lysosomal iron triggers ferroptosis in cancer

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Cañeque, Tatiana, Baron, Leeroy, Müller, Sebastian, Carmona, Alanis, Colombeau, Ludovic, Versini, Antoine, Solier, Stéphanie, Gaillet, Christine +38 more·2025·Nature
DOI 10.1038/s41586-025-08974-4PMC PMC12158755

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Abstract

Abstract Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death referred to as ferroptosis 1-3 . Identifying where this chemistry takes place in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Whereas genetic approaches have revealed underlying mechanisms of lipid peroxide detoxification 1,4,5 , small molecules can provide unparalleled spatiotemporal control of the chemistry at work 6 . Here, we show that the ferroptosis inhibitor liproxstatin-1 (Lip-1) exerts a protective activity by inactivating iron in lysosomes. Based on this, we designed the bifunctional compound fentomycin that targets phospholipids at the plasma membrane and activates iron in lysosomes upon endocytosis, promoting oxidative degradation of phospholipids and ferroptosis. Fentomycin effectively kills primary sarcoma and pancreatic ductal adenocarcinoma cells. It acts as a lipolysis-targeting chimera (LIPTAC), preferentially targeting iron-rich CD44 high cell-subpopulations 7,8 associated with the metastatic disease and drug resistance 9,10 . Furthermore, we demonstrate that fentomycin also depletes CD44 high cells in vivo and reduces intranodal tumour growth in an immunocompetent murine model of breast cancer metastasis. These data demonstrate that lysosomal iron triggers ferroptosis and that lysosomal iron redox chemistry can be exploited for therapeutic benefits.

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Authors
Cañeque, T., Baron, L., Müller, S., Carmona, A., Colombeau, L., Versini, A., Solier, S., Gaillet, C., Sindikubwabo, F., Sampaio, J. L., Sabatier, M., Mishima, E., Picard-Bernes, A., Syx, L., Servant, N., Lombard, B., Loew, D., Zheng, J., Proneth, B., Thoidingjam, L. K., Grimaud, L., Fraser, C. S., Szylo, K. J., Der Kazarian, E., Bonnet, C., Charafe-Jauffret, E., Ginestier, C., Santofimia-Castaño, P., Estaras, M., Dusetti, N., Iovanna, J. L., Cunha, A. S., Pittau, G., Hammel, P., Tzanis, D., Bonvalot, S., Watson, S., Gandon, V., Upadhyay, A., Pratt, D. A., Freitas, F. P., Friedmann Angeli, J. P., Stockwell, B. R., Conrad, M., Ubellacker, J. M., & Rodriguez, R.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Harvard University (US)
  • Helmholtz Munich (DE)
  • Inserm (FR)
  • Hôpital Paul-Brousse (FR)
  • Institut Curie (FR)
  • University of Ottawa (CA)
  • University of Würzburg (DE)
  • Columbia University (US)
Corresponding author
Rodriguez, Raphaël
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2025-05-07
Volume
642
Issue
8067
Pages
492-500
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-025-08974-4
PMC
PMC12158755
OpenAlex
W4410189348
Cited by
287
References
7
Citations by year
2026: 214 · 2025: 71 · 2024: 2
FWCI
170.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • HAL AMU (submittedVersion, cc-by)
  • HAL (submittedVersion)
Funders
  • Breast Cancer Alliance
  • Infrastructures en Biologie Santé et Agronomie
  • European Commission (647973, HORIZON2020)
  • Deutsche Forschungsgemeinschaft (CO 291/7–1, SPP2306, CO291/10-1, CO291/9-1, 428858739, 461507177, 461385412)
  • Agence Nationale de la Recherche (ANR-23-CE44-0030, ANR‐10_INBS‐04, ANR-23-IAHU-0006, ANR-10, 12015908, ANR-24-INBS-0005)
  • Institut National de la Santé et de la Recherche Médicale (21CQ016‐00)
  • Bundesministerium für Bildung und Forschung (03VP04260, 01EJ2205B)
  • Ligue Contre le Cancer
  • Institut National Du Cancer
  • Fondation Bettencourt Schueller
  • Institut de Physique du Globe de Paris (12015908)
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK128781)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
ferroptosis, lysosomal iron, liproxstatin-1, RSL3, lipid peroxidation, phospholipid oxidation, cancer cell states, drug tolerance, breast cancer metastasis, sarcoma, pancreatic ductal adenocarcinoma, cell death

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