Histone H3 lysine 18 lactylation-mediated SULF1 transcription promotes atherosclerosis by regulating endothelial-to-mesenchymal transition

Endothelial-to-mesenchymal transition (EndMT) has emerged as a pathophysiological process responsible for various chronic vascular diseases, particularly atherosclerosis. However, the molecular pathways that govern EndMT are poorly defined. This study aimed to investigate whether sulfatase-1 (SULF1) plays a role in oxidative stress-induced EndMT and atherosclerosis.

The cellular composition of the carotid atherosclerotic core was analysed using a single-cell transcriptome, followed by in vivo and in vitro validation of the underlying molecular mechanism. Single-cell transcriptome analysis revealed that SULF1 plays important roles in both EndMT and atherosclerosis. Additionally, oxidative stress promoted the upregulation of SULF1 expression in endothelial cells and induced EndMT. Notably, SULF1 overexpression promoted EndMT and exacerbated plaque instability, whereas SULF1 silencing promoted endothelial protein expression and mitigated the increase in mesenchymal proteins, effectively blocking EndMT. Subsequent experiments revealed that SULF1 induced this transition through HMOX1-induced iron overload, which further activated the WNT/SLUG pathway and promoted EndMT. Aerobic glycolysis increased in endothelium exposed to oxidative stress, accompanied by elevated lactate levels, which increased histone H3 lysine 18 lactylation (H3K18la). Mechanistically, oxidative stress significantly decreased the expression of histone deacetylase (HDAC) 3, which precisely regulated H3K18la enrichment at the SULF1 promoter, thereby activating SULF1 transcription and promoting EndMT.

This study highlights the critical role of SULF1 in EndMT and reveals precise crosstalk between metabolism and epigenetics via H3K18la by HDAC3 during EndMT-induced atherogenesis, offering novel therapeutic targets for atherosclerosis.