Nuclear factor erythroid 2-related factor 2 (NRF2) (encoded by NFE2L2 ) is a master regulator of antioxidant, metabolic, and proteostasis pathways. While protective in normal cells, constitutive NRF2 activation driven by loss-of-function mutations in KEAP1 , gain-of-function mutations in NFE2L2 , or non-mutational mechanisms is common in cancer, occurring in approximately 20%–30% of non-small cell lung cancers and at significant frequencies across multiple tumor types. In cancer, the NRF2 transcriptional program drives metabolic reprogramming, drug resistance, ferroptosis evasion, and immune exclusion making these tumors highly therapy resistant. Despite decades of effort, direct pharmacological inhibition of NRF2 has not achieved clinical success due to its structural undruggability, systemic toxicity, and context-dependent biology. This review focuses on targeting NRF2-driven metabolic dependencies as synthetic lethal vulnerabilities, spanning pathways such as glutaminolysis, redox imbalance, cystine metabolism, nucleotide biosynthesis and ER proteostasis. We also highlight emerging strategies, including allosteric KEAP1 activators, and discuss key challenges in translating these approaches into effective therapies.
Gebru et al. (Thu,) studied this question.