Abstract
Lung cancer is a leading cause of cancer-related mortality worldwide. As an age-related disease, its pathogenesis is shaped by several molecular hallmarks of aging, including impaired DNA repair and diminished stress resilience. The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) is a master regulator of oxidative stress defense and cellular survival. While NRF2 activation is protective in aging tissues, it may also be exploited by cancer cells to promote tumor progression and therapy resistance. This study aims to evaluate whether NRF2 pathway activation predicts clinical outcomes in lung cancer, with potential implications for the use of NRF2-inducing compounds. We analyzed transcriptomic and survival data from 2167 lung cancer patients using the KM Plotter database. A validated 14-gene NRF2 activation signature was used to stratify tumors by NRF2 pathway activity. Associations with overall survival (OS), first progression (FP), and post-progression survival (PPS) were assessed using Cox regression models and Kaplan-Meier analysis. High NRF2 signature expression was significantly associated with poorer OS (HR = 1.59, p = 1.3E-9), FP (HR = 1.61, p = 2.6E-5), and PPS (HR = 1.6, p = 0.002). The negative prognostic effect was most pronounced in patients with adenocarcinoma, node-negative disease, and in female patients. These findings highlight the dual role of NRF2 in promoting stress resilience and enabling cancer cell survival. NRF2 activation is a predictor of poor clinical outcomes in lung cancer. Given the widespread use of NRF2-inducing compounds such as resveratrol and sulforaphane, these findings raise important concerns about their safety in individuals at risk for or living with cancer. Our results underscore the importance of context-specific evaluation of NRF2-targeted interventions and caution against the indiscriminate use of NRF2-activating agents in aging populations, particularly in individuals at risk for lung cancer.