NSUN2, a key RNA m5C methyltransferase, is highly expressed in non-small cell lung cancer (NSCLC) and correlates with poor patient outcomes. This study reveals that NSUN2 promotes ferroptosis resistance in NSCLC by enhancing NRF2 expression through m5C modification of NRF2 mRNA. NSUN2 increases NRF2 stability via the m5C-YBX1 axis, which is crucial for maintaining NRF2 expression and resisting ferroptosis. Knockdown of NSUN2 reduces NRF2 expression and increases sensitivity to ferroptosis inducers, suggesting that targeting NSUN2 could be a promising therapeutic strategy for NSCLC. NSUN2 overexpression enhances NSCLC cell proliferation, migration, and invasion, while its deficiency inhibits these processes. NSUN2-mediated m5C modification of NRF2 mRNA stabilizes NRF2, which is essential for antioxidant defense and resistance to ferroptosis. The study highlights the NSUN2-NRF2-YBX1 axis as a novel regulatory mechanism in NSCLC, offering potential therapeutic targets for improving treatment outcomes.NSUN2, a key RNA m5C methyltransferase, is highly expressed in non-small cell lung cancer (NSCLC) and correlates with poor patient outcomes. This study reveals that NSUN2 promotes ferroptosis resistance in NSCLC by enhancing NRF2 expression through m5C modification of NRF2 mRNA. NSUN2 increases NRF2 stability via the m5C-YBX1 axis, which is crucial for maintaining NRF2 expression and resisting ferroptosis. Knockdown of NSUN2 reduces NRF2 expression and increases sensitivity to ferroptosis inducers, suggesting that targeting NSUN2 could be a promising therapeutic strategy for NSCLC. NSUN2 overexpression enhances NSCLC cell proliferation, migration, and invasion, while its deficiency inhibits these processes. NSUN2-mediated m5C modification of NRF2 mRNA stabilizes NRF2, which is essential for antioxidant defense and resistance to ferroptosis. The study highlights the NSUN2-NRF2-YBX1 axis as a novel regulatory mechanism in NSCLC, offering potential therapeutic targets for improving treatment outcomes.