The KEAP1-NFE2L2/NRF2 Axis in Non-Small Cell Lung Cancer Radioresistance: Redox Homeostasis and Emerging DNA Damage Response Mechanisms.
Radioresistance and local recurrence remain major barriers to effective radiotherapy in non-small cell lung cancer (NSCLC). Loss-of-function KEAP1 alterations or activating NFE2L2 alterations can stabilize NRF2, but do not alone establish sustained transcriptional activity or functional dependency. This focused narrative review evaluates clinical radiotherapy studies and mechanistically informative preclinical studies linking the KEAP1-NFE2L2/NRF2 axis to NSCLC radioresistance. We prioritized clinical studies reporting radiotherapy-specific outcomes and preclinical studies coupling NRF2-related molecular status or perturbation with radiation-response endpoints; contextual studies informed metabolic, DNA damage response (DDR), immune and normal-lung effects. Evidence most consistently supports NRF2-mediated redox protection through glutathione-dependent defense, cellular reducing capacity and antioxidant enzymes, limiting radiation-induced reactive oxygen species (ROS) accumulation and oxidative injury. Limited studies further suggest that NRF2 may affect DNA-damage signaling, checkpoint control and repair. The detailed RPA32-TOPBP1-ATR-CHK1 model is therefore considered proposed rather than established in NRF2-active NSCLC. Retrospective clinical studies associate pathogenic KEAP1/NFE2L2 alterations with impaired local control in some radiotherapy-treated cohorts, but do not justify treating genomic status, protein abundance, transcriptional activity and functional dependency as equivalent measures or demonstrate treatment-predictive value. NRF2-mediated normal-lung protection also constrains systemic inhibition. Prospective studies integrating molecular classification, radiation-response endpoints, local control and normal-tissue toxicity are required before biomarker-guided radiosensitization can be considered.