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

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.