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Lysine Lactylation (Kla), a novel posttranslational modification, critically regulates inflammation, tumors, and cardiovascular diseases. However, its specific role in AD pathogenesis remains unexplored. Using modification omics, we conducted a macroscopic analysis of the occurrence of extensive lactylation modification in aortic dissection and identified extensive lactylation, particularly in the adenosine triphosphatase activity pathway. Among these proteins, adenosine triphosphate (ATP) synthase F1 subunit \u03b1 (ATP5F1A), a subunit in the ATP synthase complex, exhibited pronounced lactylation at the K531, catalyzed by sirtuin 3 (Sirt3). Through site-directed mutagenesis (K531R\/K531E), we validated the key mechanism of lactylation activation at the K531 site of ATP5F1A and the regulatory enzymes. Functionally, K531 lactylation impairs ATP synthase activity, elevates reactive oxygen species generation, reduces ATP generation, and induces mitochondrial structural abnormalities. These effects ultimately contribute to the phenotypic transformation of human aortic vascular smooth muscle cells and enhanced synthesis and secretion of matrix metalloproteinases. In addition, we assessed the potential therapeutic effect of lactylation inhibition in aortic dissection using a mouse model and a drug based in\u00a0vivo lactate alteration strategy. In conclusion, targeting the lactate\u2013Sirt3\u2013ATP5F1A axis represents a promising therapeutic strategy for blocking the progression of aortic dissection.<\/jats:p>","DOI":"10.34133\/research.0799","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T03:24:58Z","timestamp":1751599498000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":23,"title":["Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic Dissection"],"prefix":"10.34133","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0925-2242","authenticated-orcid":false,"given":"Tao","family":"Yu","sequence":"first","affiliation":[{"name":"Institute for Translational Medicine, The Affiliated Hospital of Qingdao University","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8860-7303","authenticated-orcid":false,"given":"Xiaolu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiac Ultrasound, \rThe Affiliated hospital of Qingdao University, Qingdao 266000, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, \rThe Affiliated Hospital of Qingdao University, Qingdao, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, \rQingdao University, Qingdao 266071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuxiu","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Cardiac Ultrasound, \rThe Affiliated hospital of Qingdao University, Qingdao 266000, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxiang","family":"Li","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine, The Affiliated Hospital of Qingdao University","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine, The Affiliated Hospital of Qingdao University","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine, The Affiliated Hospital of Qingdao University","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine, The Affiliated Hospital of Qingdao University","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of General Medicine, \rThe Affiliated Hospital of Qingdao University, Qingdao 266000, People\u2019s Republic of China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3731-6514","authenticated-orcid":true,"given":"Jian-Xun","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine, The Affiliated Hospital of Qingdao University","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2025,8,12]]},"reference":[{"issue":"7","key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1001\/jama.283.7.897","article-title":"The international registry of acute aortic dissection (IRAD): New insights into an old disease","volume":"283","author":"Hagan PG","year":"2000","unstructured":"Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, Evangelista A, Fattori R, Suzuki T, Oh JK, et al. 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