Targeting NRF2 and FSP1 to overcome ferroptosis resistance in TSC2-deficient and cancer cells

Tahsin, Tasmia, McPhail, Darius K., Champion, Jesse D., Alzahrani, Mohammad A. M., Hilditch, Madeleine L., Faris-Orr, Alexandre, Calver, Brian L., Cronin, James G., Mareque-Rivas, Juan C., Sexton, Darren W., Hughes, Stephen Fôn, Conlan, Robert Steven, Davies, David Mark and Tee, Andrew R. 2025. Targeting NRF2 and FSP1 to overcome ferroptosis resistance in TSC2-deficient and cancer cells. Cancers 17 (16) , 2714. 10.3390/cancers17162714

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Abstract

Cancer treatments often aim to induce cell death, but many tumors develop resistance to conventional therapies such as chemotherapy. Ferroptosis is a distinct, iron-dependent form of cell death that offers a promising alternative for overcoming this resistance. In this study, we investigated how cancer cells resist ferroptosis, focusing on models with elevated iron metabolism. Using Tuberous Sclerosis Complex 2 (TSC2)-deficient cells, as well as ovarian and breast cancer cell lines, we found that these cells were resistant to ferroptosis. However, this resistance could be reversed by inhibiting key antioxidant proteins. Our study points to new therapeutic strategies that target ferroptosis resistance mechanisms, offering potential treatments for otherwise difficult-to-treat cancers.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Publisher:	MDPI
ISSN:	2072-6694
Funders:	Cancer Research Wales
Date of First Compliant Deposit:	21 August 2025
Date of Acceptance:	19 August 2025
Last Modified:	22 Aug 2025 08:45
URI:	https://orca.cardiff.ac.uk/id/eprint/180592

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