{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:53:14Z","timestamp":1787071994080,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Shanghai","award":["22ZR1412100"],"award-info":[{"award-number":["22ZR1412100"]}]},{"name":"Qingpu Hospital Affiliated to Fudan University General Program","award":["QYBS2025-02"],"award-info":[{"award-number":["QYBS2025-02"]}]},{"award":["QYBS2025-02"],"award-info":[{"award-number":["QYBS2025-02"]}],"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Accumulation of senescent endothelial cells (ECs) accelerates atherosclerosis, yet the molecular orchestrators linking metabolic dysregulation to epigenetic reprogramming during EC senescence remain elusive. Here, we investigated the specific role of Myeloid cell leukemia 1 (MCL1) in endothelial senescence and atherogenesis. Through integrative bioinformatics, MCL1 was identified as a candidate senescence regulator. MCL1 expression was validated in human carotid atherosclerotic plaques, ApoE\u2212\/\u2212 mice, and multiple EC senescence models, primarily HRASG12V-induced senescent human umbilical vein endothelial cells (HUVECs). Loss- and gain-of-function assays were performed in HUVECs. Underlying metabolic and epigenetic mechanisms were explored using Seahorse extracellular flux analysis, lactate measurements, Co-IP and CUT&amp;Tag sequencing. In vivo therapeutic potential was evaluated via AAV-mediated MCL1 knockdown in high-fat diet-fed ApoE\u2212\/\u2212 mice. MCL1 expression was significantly upregulated in atherosclerotic plaques and senescent ECs. Functionally, MCL1 knockdown attenuated senescence markers (SA-\u03b2-gal, P21), suppressed the senescence-associated secretory phenotype (SASP), and restored cell proliferation, whereas MCL1 overexpression exacerbated EC senescence. Mechanistically, MCL1 promoted glycolytic reprogramming and intracellular lactate accumulation. This metabolic byproduct served as an epigenetic substrate for histone H4K12 lactylation (H4K12la), which specifically enriched at the CDKN1A (P21) promoter, correlating with its transcription. In vivo, AAV-mediated MCL1 silencing effectively reduced vascular H4K12la levels, alleviated vascular senescence, and substantially constrained atherosclerotic lesion areas. Our findings identify MCL1 as a pivotal regulator of endothelial senescence and atherosclerosis, operating through a metabolic-\\\u2013epigenetic mechanism involving glycolytic reprogramming, lactate accumulation, and H4K12la-associated P21 upregulation. These findings suggest that targeting the MCL1-associated pathway may represent a potential therapeutic strategy for atherosclerosis.<\/jats:p>","DOI":"10.3390\/ijms27167392","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:12:11Z","timestamp":1787069531000},"page":"7392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MCL1 Promotes Endothelial Senescence and Atherosclerosis via Glycolytic Reprogramming-Induced H4K12 Lactylation"],"prefix":"10.3390","volume":"27","author":[{"given":"Yang","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Vascular Surgery, Zhongshan Clinical Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Vascular Surgery, Zhongshan Clinical Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Vascular Surgery, Zhongshan Clinical Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yakun","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Vascular Surgery, Zhongshan Clinical Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanying","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Vascular Surgery, Zhongshan Clinical Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longhua","family":"Fan","sequence":"additional","affiliation":[{"name":"Institute of Vascular Surgery, Zhongshan Clinical Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1161\/ATVBAHA.118.311999","article-title":"Highlighting Residual Atherosclerotic Cardiovascular Disease Risk","volume":"39","author":"Matsuura","year":"2019","journal-title":"Arterioscler. 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