NRF2-Regulated Ferroptosis in Breast Cancer: Mechanisms, Resistance, and Therapeutic Opportunities.

Authors

Suleiman Ibrahim Mohammad, Asokan Vasudevan, Samreet Raizal Rodrigues, Rustam Turakulov, Mirza R Baig, Ozodbek Nematov, Navin Kumar Tailor, Divya Singhal, Priya Priyadarshini Nayak

Published in

Asia-Pacific journal of clinical oncology. Sep 27, 2026. Epub Sep 27, 2026.

Abstract

Breast cancer remains a significant clinical challenge, particularly in triple‑negative breast cancer (TNBC), in which therapeutic resistance limits treatment efficacy. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising strategy to overcome resistance in breast cancer. Among the principal nodulators of ferroptosis, NRF2 functions as a central antioxidant transcription factor that suppresses ferroptotic death by promoting glutathione metabolism and cystine uptake via SLC7A11/system Xc-, while also supporting GPX4-dependent lipid peroxide detoxification and iron-sequestering defenses such as FTH1/FTL. In breast cancer, aberrant NRF2 activation supports tumor progression, survival, stemness, immune evasion, and resistance to chemotherapy, radiotherapy, and targeted therapies. This review summarizes the molecular mechanisms by which NRF2 regulates ferroptosis, including KEAP1-NRF2 signaling, metabolic rewiring, iron homeostasis, lipid remodeling, and crosstalk with p53 and other stress-response pathways. We also highlight key regulators such as PRMT5, NUP62, NR5A2/NCOA3, miR-141-3p, DHODH, and ACSL4/ALOX enzymes that shape ferroptosis sensitivity. Furthermore, the review discusses emerging therapeutic approaches aimed at restoring ferroptotic vulnerability, including direct NRF2 inhibitors, natural products, metal-based compounds, repurposed drugs, and nanotechnology-enabled delivery systems. TNBC is specifically reliant on NRF2-driven antioxidant defenses to maintain redox homeostasis and resist ferroptotic stress, supporting its prioritization as a target population for NRF2-ferroptosis-based therapeutic methods. Collectively, targeting the NRF2-ferroptosis axis offers a compelling avenue for improving breast cancer treatment, especially in resistant and aggressive subtypes such as TNBC.

PMID:
42802387
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.

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