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Targeting NRF2 and FSP1 to Overcome Ferroptosis Resistance in TSC2-Deficient and Cancer Cells
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Jesse D. Champion,
Mohammad A. M. Alzahrani,
Madeleine L. Hilditch,
Alexandre Faris-Orr,
Brian L. Calver,
James Cronin ,
Juan C. Mareque-Rivas,
Darren W. Sexton ,
Stephen Fôn Hughes ,
Steve Conlan ,
David Mark Davies,
Andrew R. Tee
Cancers, Volume: 17, Issue: 16, Start page: 2714
Swansea University Authors:
James Cronin , Steve Conlan
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DOI (Published version): 10.3390/cancers17162714
Abstract
Background/Objectives: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and holds promise as a therapeutic strategy against cancers with elevated iron metabolism. However, many tumors evade ferroptosis through the upregulation of specialized antioxidant defe...
| Published in: | Cancers |
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| ISSN: | 2072-6694 |
| Published: |
MDPI AG
2025
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70650 |
| Abstract: |
Background/Objectives: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and holds promise as a therapeutic strategy against cancers with elevated iron metabolism. However, many tumors evade ferroptosis through the upregulation of specialized antioxidant defense mechanisms. Here, we investigated ferroptosis susceptibility and resistance mechanisms in TSC models and in ovarian and breast cancer cell lines, aiming to identify potential therapeutic targets. Methods: Ferroptosis sensitivity was assessed using RSL3 and erastin. We explored the contribution of ferroptosis defense pathways using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA sequencing was performed to evaluate the expression of ferroptosis resistance genes and to explore NRF2-regulated transcriptional programs. Results: TSC2-deficient cells were resistant to RSL3- and erastin-induced ferroptosis. This resistance correlated with upregulation of ferroptosis defense genes, including NRF2 and its downstream targets. Pharmacological inhibition of NRF2 resensitized TSC2-deficient cells to ferroptosis, confirming a protective role for NRF2. However, FSP1 inhibition did not restore ferroptosis sensitivity in TSC2-deficient angiomyolipoma cells. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cells. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition to enhance ferroptosis sensitivity. FSP1 expression was not regulated by NRF2, suggesting that NRF2-targeted therapies alone may be insufficient to overcome ferroptosis resistance in certain cancer contexts. Conclusions: TSC2-deficient cells resist ferroptosis via an adaptive antioxidant response that protects against elevated iron-mediated lipid peroxidation. Our findings identify NRF2 and FSP1 as key, but mechanistically distinct, regulators of ferroptosis resistance. The differential efficacy of targeting these pathways across cancer types highlights the potential need for patient stratification. Dual targeting of NRF2 and FSP1 may offer an effective therapeutic strategy for iron-dependent, ferroptosis-resistant cancers. |
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| Keywords: |
ferroptosis; tuberous sclerosis complex; mTOR; cancer resistance; NRF2; FSP1; RSL3 |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This research was funded by Welsh Government’s European Social Fund (ESF) convergence programme for West Wales and the Valleys KESS II and BCUHB to T.T., S.F.H., R.S.C., D.M.D. and A.R.T.; Cancer Research Wales PhD studentship, grant number 2504 to D.K.M., D.M.D. and A.R.T.; Cancer Research Wales Fellowship, grant number 2527 to D.K.M., J.G.C., J.C.M., D.M.D. and A.R.T.; Tuberous Sclerosis Association, grant number 2018-S04 to J.D.C., D.M.D. and A.R.T.; King Fahd Security College/Ministry of Interior/Saudi Arabia, grant number 1050795978 to M.A.M.A. and A.R.T.; and Health and Care Research Wales (Wales Gene Park), grant number R21CA263133 to A.R.T. |
| Issue: |
16 |
| Start Page: |
2714 |