FTO mediates benzo[a]pyrene-induced lung cancer progression through regulating ferroptosis via lactylation-driven YTHDF2-KEAP1-NRF2 axis.

N6-methyladenosine (m6A) RNA modification and histone lactylation are important regulators of gene expression and cancer progression, but their interplay in lung cancer associated with benzo[a]pyrene (BaP) remains unclear. Integrating clinical bioinformatics with cellular and in vivo analyses, we found that BaP enhanced migration and invasion while inducing a ferroptosis-resistant phenotype in lung cancer cells. Pharmacological modulation with Erastin and Ferrostatin-1 further supported ferroptosis involvement. BaP decreased FTO and increased YTHDF2 expression. FTO overexpression and YTHDF2 knockdown enhanced ferroptosis-associated lipid oxidation and suppressed migration and invasion, while their combined intervention attenuated BaP-associated experimental metastatic progression in vivo. Mechanistically, FTO overexpression reduced m6A enrichment on KEAP1 mRNA, whereas YTHDF2 associated with KEAP1 transcripts and accelerated their decay. Disruption of the A2108 RRACH motif attenuated YTHDF2-responsive repression of the KEAP1 reporter. KEAP1 knockdown attenuated FTO effects under BaP exposure. Upstream analyses supported AHR-dependent FTO regulation and a glycolysis-associated lactate-H3K18la contribution to YTHDF2 upregulation. Collectively, these findings support an m6A-sensitive FTO/YTHDF2-KEAP1-NRF2 framework contributing to ferroptosis defense and BaP-associated lung cancer malignant progression.