Atherosclerosis is a chronic inflammatory vascular disease driven by endothelial-to-mesenchymal transition (EndMT). This study reveals that lipid peroxidation promotes EndMT by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la). The histone chaperone ASF1A, identified as a cofactor of P300, precisely regulates H3K18la at the SNAI1 promoter, activating SNAI1 transcription and promoting EndMT. ASF1A deletion inhibits EndMT and improves endothelial dysfunction. In atherosclerosis models, endothelium-specific ASF1A deficiency reduces EndMT and alleviates atherosclerosis. Pharmacological inhibition of glycolysis and PROTACs reduce H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. The study highlights the crosstalk between metabolism and epigenetics via H3K18la mediated by the P300/ASF1A complex during EndMT, offering new therapeutic strategies for atherosclerosis.Atherosclerosis is a chronic inflammatory vascular disease driven by endothelial-to-mesenchymal transition (EndMT). This study reveals that lipid peroxidation promotes EndMT by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la). The histone chaperone ASF1A, identified as a cofactor of P300, precisely regulates H3K18la at the SNAI1 promoter, activating SNAI1 transcription and promoting EndMT. ASF1A deletion inhibits EndMT and improves endothelial dysfunction. In atherosclerosis models, endothelium-specific ASF1A deficiency reduces EndMT and alleviates atherosclerosis. Pharmacological inhibition of glycolysis and PROTACs reduce H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. The study highlights the crosstalk between metabolism and epigenetics via H3K18la mediated by the P300/ASF1A complex during EndMT, offering new therapeutic strategies for atherosclerosis.