Multi-omics reveals crosstalk between lactylation and m6A methylation promotes angiogenesis in lung adenocarcinoma

Abstract Bevacizumab (Bev) is pivotal in metastatic lung adenocarcinoma (LUAD) therapy, though lactate's regulatory mechanisms remain incompletely characterized. We reveal significant lactate accumulation in Bev-resistant tumors, driving elevated histone lactylation. EZH2-mediated glycolysis enhances lactylation, repressing TIMP2 transcription to promote mitochondrial transfer between endothelial and malignant cells, thereby accelerating angiogenesis and metastasis. Lactate further induces YTHDF2 K17-lactylation, enhancing nuclear translocation and m⁶A recognition to stabilize EZH2 mRNA. FTO suppresses EZH2 via m⁶A demethylation, negatively regulating glycolysis. Clinical data associate high lactylation with poor prognosis. Dual targeting of lactylation and m⁶A combined with Bev demonstrates potent efficacy. These findings provide novel insights into epigenetic mechanisms of metabolic reprogramming and offer therapeutic strategies for patients with Bev-refractory LUAD.