This study investigates the role of histone H3 lysine 18 lactylation (H3K18la) in endothelial-to-mesenchymal transition (EndMT) and atherosclerosis. The authors found that lipid peroxidation-induced EndMT is promoted by increased lactate production, which leads to elevated H3K18la levels. H3K18la is enriched at the promoter region of SNAI1, a key transcription factor in EndMT, and increases its expression. The P300 histone acetyltransferase and histone chaperone ASF1A form a complex that cooperates to regulate H3K18la, thereby enhancing EndMT and atherosclerosis. The study also demonstrates that reducing ASF1A expression, inhibiting glycolysis, or using PROTACs to target HK2 can attenuate H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. These findings highlight a novel mechanism by which metabolic disturbances and epigenetic regulation interact to promote atherosclerosis.This study investigates the role of histone H3 lysine 18 lactylation (H3K18la) in endothelial-to-mesenchymal transition (EndMT) and atherosclerosis. The authors found that lipid peroxidation-induced EndMT is promoted by increased lactate production, which leads to elevated H3K18la levels. H3K18la is enriched at the promoter region of SNAI1, a key transcription factor in EndMT, and increases its expression. The P300 histone acetyltransferase and histone chaperone ASF1A form a complex that cooperates to regulate H3K18la, thereby enhancing EndMT and atherosclerosis. The study also demonstrates that reducing ASF1A expression, inhibiting glycolysis, or using PROTACs to target HK2 can attenuate H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. These findings highlight a novel mechanism by which metabolic disturbances and epigenetic regulation interact to promote atherosclerosis.