The impact of oxidative stress and the NRF2-KEAP1-ARE signaling pathway on anticancer drug resistance

Cancer remains a major global health burden, with rising incidence and mortality linked to aging populations and increased exposure to genotoxic agents. Oxidative stress plays a critical role in cancer development, progression, and resistance to therapy. The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1)-antioxidant response element (ARE) signaling pathway is central to maintaining redox balance by regulating the expression of antioxidant and detoxification genes. Under physiological conditions, this pathway protects cells from oxidative damage, however, sustained activation of NRF2 in cancer, often due to mutations in KEAP1, supports tumor cell survival, drug resistance, and metabolic reprogramming. Recent studies demonstrate that NRF2 enhances glutathione (GSH) synthesis, induces detoxifying enzymes, and upregulates drug efflux transporters, collectively contributing to resistance against chemotherapy and targeted therapies. The inhibition of NRF2 using small molecules or dietary phytochemicals has shown promise in restoring drug sensitivity in preclinical cancer models. This review highlights the dual role of NRF2 in redox regulation and cancer therapy, emphasizing its potential as a therapeutic target. While targeting NRF2 offers a novel approach to overcoming treatment resistance, further research is needed to enhance specificity and facilitate clinical translation.