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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\u2010CoA, and regulated by CBP and SIRT2 in vivo. Multi\u2010omics 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\u2010related outcomes. Collectively, we discover a new histone mark with potential physiological relevance and may reveal a previously unrecognized mechanism underlying the non\u2010canonical functions of aspirin.<\/jats:p>","DOI":"10.1002\/advs.77838","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:51:27Z","timestamp":1789620687000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aspirin\u2010Derived Salicyl\u2010CoA Drives Histone Lysine Salicylation Regulated by CBP and SIRT2"],"prefix":"10.1002","author":[{"given":"Facai","family":"Zhang","sequence":"first","affiliation":[{"name":"Urology &amp; Nephrology Center Department of Urology Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College  Hangzhou China"},{"name":"Life Sciences Institute The MOE Key Laboratory of Biosystems Homeostasis and Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology Zhejiang University  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2904-1294","authenticated-orcid":false,"given":"Chuanzan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Urology &amp; 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