Mechanistically, GAS41 interacted with NRF2 and promoted NRF2 transcriptional ability, specifically on glutathione (GSH) metabolism genes, SLC7A11 and GCLC. Our study underlines a mechanism for NRF2 transcriptional regulation and provides a potential method for NSCLC therapy through targeting GAS41-mediated ferroptosis defense. The gene discussed is NFE2L2; the disease is non-small cell lung carcinoma.