SLC22A6-dependent lactylation of H3K9 aggravates endothelial dysfunction and atherosclerosis

Atherosclerosis, a leading cause of cardiovascular morbidity and mortality, is driven by endothelial dysfunction. While metabolic reprogramming toward glycolysis in endothelial cells exacerbates disease progression, the role of lactate-derived lactylation in atherogenesis remains poorly understood.

We performed RNA-seq on aortic tissues from atherosclerotic mice to identify differentially expressed genes, along with Seahorse XF metabolic flux analysis. Endothelium-specific solute carrier family 22 member 6 (Slc22a6) knockout and AAV-delivered acyl-CoA synthetase short-chain family member 1 (Acss1) knockdown mice were established on an ApoE^KO background. Integrated multi-omics (RNA-seq, CUT&Tag, metabolomics) elucidated downstream regulatory networks, and in vivo pharmacological inhibition validated key pathways.

Our study reveals a marked elevation of histone H3 Lysine 9 Lactylation (H3K9la) relative to acetylation in atherosclerotic aortic tissue, potentially via SLC22A6-mediated glycolytic enhancement and lactate uptake. Additionally, endothelial-specific knockout of Slc22a6 attenuates H3K9la-driven endothelial dysfunction and atherosclerosis. Integrated RNA-seq and CUT&Tag analyses identify that upregulated ACSS1 and E1A binding protein p300 (EP300) drive H3K9la, which transcriptionally activates stearoyl-CoA desaturase 1 (SCD1), thereby exacerbating endothelial dysfunction. Pharmacological inhibition of H3K9la or SCD1 alleviates endothelial dysfunction and atherosclerosis in vitro and in vivo. We further establish the clinical relevance of lactate, SLC22A6, and ACSS1 in atherosclerosis.

Our findings unveil a metabolism-epigenetics-transcription regulatory axis in endothelial pathophysiology, thus providing novel therapeutic strategies for atherosclerosis by targeting the SLC22A6-dependent ACSS1-H3K9la-SCD1 pathway.