The m6A Reader IGF2BP2 Suppresses Ferroptosis in Nasopharyngeal Carcinoma by Stabilizing NRF2 mRNA

Nuclear factor erythroid 2-related factor 2 (NRF2) is a central transcriptional regulator of the antioxidant response and a key inhibitor of ferroptosis, and its overexpression is frequently observed in various cancers. However, the mechanisms underlying its dysregulation in nasopharyngeal carcinoma (NPC) remain poorly understood. In this study, we combined bioinformatic analysis with functional experiments to investigate the post‑transcriptional regulation of NRF2 in NPC. Using weighted gene co-expression network analysis (WGCNA) based on the GSE68799 dataset and differential expression analysis of NPC transcriptomic data, we identified NRF2 as a candidate gene associated with NPC progression. Functional studies confirmed that NRF2 inhibits ferroptosis in NPC cells. Mechanistically, we demonstrated that the m6A reader protein insulin‑like growth factor 2 mRNA‑binding protein 2 (IGF2BP2) binds to and stabilizes NRF2 mRNA in an m6A‑dependent manner. Depletion of IGF2BP2 downregulated NRF2 expression and accelerated NRF2 mRNA decay. Notably, inhibition of methyltransferase activity by S-Adenosyl-L-homocysteine (SAH) reduced m6A modification on NRF2 mRNA and impaired its interaction with IGF2BP2. Furthermore, IGF2BP2 knockdown impaired the NRF2/HO-1/GPX4 axis, leading to a significant reduction in GPX4 enzymatic activity and promoted ferroptosis, effects that were rescued by the NRF2 activator dimethyl fumarate (DMF). Collectively, these results reveal that IGF2BP2 stabilizes NRF2 mRNA via m6A modification to suppress ferroptosis, thereby promoting NPC cell survival.