Aspirin‐Derived Salicyl‐CoA Drives Histone Lysine Salicylation Regulated by CBP and SIRT2

Aspirin, as the most widely used drug in the world, has been reported to exert antiplatelet, anti-inflammatory, and anti-tumor effects. However, apart from the hydrolyzed acetyl group acetylating proteins, and salicylic acid functioning as a classic COX enzyme inhibitor, it is unknown whether the salicylic group of aspirin could participate in the salicylation of histone lysine. Herein, we discover and characterize lysine salicylation (Ksa) in histone and 39 Ksa sites of histone were mapped in 3 cell lines. Ksa could be stimulated by aspirin via direct action and conversion to salicyl-CoA, and regulated by CBP and SIRT2 in vivo. Multi-omics analyses reveal associations between histone Ksa enrichment and transcriptional changes in physiologically relevant genes. Moreover, immunohistochemistry of Ksa levels in bladder cancer tissues are associated with aspirin exposure and show a preliminary correlation with recurrence-related outcomes. Collectively, we discover a new histone mark with potential physiological relevance and may reveal a previously unrecognized mechanism underlying the non-canonical functions of aspirin.