Balancing Act: NRF2's contradictory roles in cancer progression and therapy

The nuclear factor erythroid 2-related factor 2 (NRF2) is an important cellular defense factor that regulates antioxidant and detoxifying gene expression. While NRF2 protects cells from oxidative stress, misregulation has been associated with cancer growth. Mutations in NRF2 or its inhibitor Kelch-like ECH-associated protein 1 can cause prolonged activation, which promotes tumor development, chemoresistance, and cancer cell survival. Understanding the NRF2 pathway is critical for designing targeted therapeutics, especially in cancers including lung, breast, and esophageal cancer, where NRF2 overexpression is associated with a poor prognosis and treatment resistance. The potential of NRF2 inhibitors in overcoming chemoresistance emphasizes their importance as a therapeutic target in cancer treatment. This review examines the molecular structure and regulatory mechanisms of NRF2, highlighting its dual role as both a tumor suppressor and an oncogene.