Ferroptosis and Nrf2 Signaling in Head and Neck Cancer: Resistance Mechanisms and Therapeutic Prospects
Abstract
1. Introduction
2. Molecular Interplay Between Ferroptosis and Nrf2 Signaling
3. The Role of Nrf2 in Ferroptosis Evasion in Head and Neck Cancer
4. Mechanistic Determinants of Ferroptosis Resistance in Head and Neck Cancer
4.1. RNA Epigenetic Regulation and the m6A Machinery
4.2. Oncoviral Reprogramming via the Nrf2 Pathway
4.3. Platelet-Derived Extracellular Vesicles and Intercellular Crosstalk
4.4. Epigenetic Stabilization of Nrf2 by PRMT4
4.5. Paracrine Activation by Cancer-Associated Fibroblasts
4.6. The SLC7A11–GSH–GPX4 Axis in Redox Compensation
4.7. Thioredoxin Reductase 1 (TXNRD1) and Immune Evasion
4.8. KEAP1 Mutation, NQO1 Upregulation, and Ferroptosis–Immune Resistance Axis
5. Ferroptosis Modulation as a Therapeutic Strategy in Head and Neck Cancer
6. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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Compound/Modulator | Mechanism of Action | HNC Subtype/Model | Therapeutic Insight | Reference(s) |
---|---|---|---|---|
Auranofin | Inhibits TXNRD1; suppresses Nrf2 signaling; enhances CD8+ T-cell infiltration | HNSCC (PD-L1+, resistant models) | Synergizes with anti-PD-1 therapy; ferroptosis and immunotherapy sensitization. | [33] |
Fucoxanthin | Downregulates GPX4, SLC7A11, and Nrf2; increases ROS, MDA, and iron | SCC-25 (tongue SCC cells) | Induces mitochondrial damage and ferroptosis via redox and iron pathway disruption. | [71] |
Carnosic acid | Inhibits the Nrf2–HO-1–SLC7A11 pathway; increases lipid peroxidation | CAL27-DDP, SCC9-DDP (cisplatin-resistant OSCC) | Reverses cisplatin resistance; promotes ferroptotic sensitivity in resistant OSCC cells. | [72] |
Disulfiram/Cu (DSF/Cu) | Increases labile iron and lipid peroxidation; counteracted by Nrf2–HO-1 activation | OSCC cell lines; xenograft models | Nrf2 inhibition enhances DSF/Cu cytotoxicity and ferroptosis induction. | [48] |
Trigonelline | Suppresses Nrf2–ARE signaling; reduces HO-1; restores lipid peroxidation | HNC cisplatin-resistant models | Enhances ferroptosis by sensitizing cells to artesunate and GPX4 inhibitors; tumor-selective redox modulation. | [27,28] |
NQO1 (KEAP1-deficient context) | NRF2 target gene; induces ferroptosis; triggers antitumor immune activation | HNSCC (KEAP1-deficient and immunotherapy-resistant) | Overcomes ferroptosis and immune resistance via NQO1-mediated ferroptosis; potential biomarker for immunotherapy sensitivity. | [34] |
FGF5/FGFR2 (CAF-derived) | Activates Keap1–Nrf2–HO-1 signaling; blocks ferroptosis | NPC (CAF co-culture and in vivo models) | Stromal signaling promotes redox resistance; targeting FGFR2 restores cisplatin-induced ferroptosis. | [30] |
ALKBH5/IGF2BP2 axis | Stabilizes Nrf2 mRNA via m6A demethylation; suppresses ferroptosis | Hypopharyngeal SCC | RNA methylation-dependent ferroptosis resistance; epitranscriptomic therapeutic target. | [29] |
Platelet EVs / ITGB3 | Activates MAPK/ERK/ATF4/Nrf2; increases SLC7A11 and suppresses lipid peroxidation | NPC cell lines and xenograft models | EV-mediated intercellular ferroptosis evasion; targeting EV signaling restores redox imbalance | [31] |
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Lee, J.; Seo, Y.; Roh, J.-L. Ferroptosis and Nrf2 Signaling in Head and Neck Cancer: Resistance Mechanisms and Therapeutic Prospects. Antioxidants 2025, 14, 993. https://doi.org/10.3390/antiox14080993
Lee J, Seo Y, Roh J-L. Ferroptosis and Nrf2 Signaling in Head and Neck Cancer: Resistance Mechanisms and Therapeutic Prospects. Antioxidants. 2025; 14(8):993. https://doi.org/10.3390/antiox14080993
Chicago/Turabian StyleLee, Jaewang, Youngin Seo, and Jong-Lyel Roh. 2025. "Ferroptosis and Nrf2 Signaling in Head and Neck Cancer: Resistance Mechanisms and Therapeutic Prospects" Antioxidants 14, no. 8: 993. https://doi.org/10.3390/antiox14080993
APA StyleLee, J., Seo, Y., & Roh, J.-L. (2025). Ferroptosis and Nrf2 Signaling in Head and Neck Cancer: Resistance Mechanisms and Therapeutic Prospects. Antioxidants, 14(8), 993. https://doi.org/10.3390/antiox14080993