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BMAL1 dysregulation is associated with apoptosis. However, it remains elusive whether BMAL1 dysregulation may aggravate VSMC apoptosis to participate in the development of TAAD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Transcriptomic analysis and molecular assays were performed to analyse BMAL1 level in the TAAD patients and 3-aminopropionitrile fumarate (BAPN)-induced TAAD mice. Global and VSMC-specific BMAL1 haploinsufficient mice were used to determine the role of BMAL1 in BAPN-induced TAAD murine model. Transcriptomics, spatial transcriptomics, histological, and in vitro experiments were performed to examine the underlying mechanisms. BMAL1 level was reduced in the thoracic aorta from TAAD patients and BAPN-challenged mice. Global and VSMC-specific BMAL1 haploinsufficiency significantly increased the risk of BAPN-induced TAAD in mice. BMAL1 dysregulation induced VSMC apoptosis during challenge-induced TAAD formation. Moreover, BMAL1 transcriptionally regulated REV-ERB\u03b1 by binding to the E-box in its promoter region. Overexpression of REV-ERB\u03b1 alleviated the detrimental effect of BMAL1 dysregulation on the formation of TAAD and VSMC apoptosis. Conversely, REV-ERB\u03b1 dysregulation aggravated TAAD and VSMC apoptosis. Mechanistically, VSMC apoptosis inducer c-MYC was regulated by BMAL1\/REV-ERB\u03b1 axis and was proven as a direct target of REV-ERB\u03b1. Importantly, BMAL1 activator ISX-9 and REV-ERB\u03b1 agonist SR9009 reduced the risk of BAPN-induced TAAD in both BMAL1 haploinsufficient and control mice, even when they were administered from 14 days after BAPN modeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>BMAL1 insufficiency increases the risk of TAAD by inducing VSMC apoptosis via down-regulation of REV-ERB\u03b1. BMAL1 and REV-ERB\u03b1 may serve as pharmacological targets for TAAD prevention and therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf259","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T13:39:00Z","timestamp":1763645940000},"page":"146-161","source":"Crossref","is-referenced-by-count":5,"title":["BMAL1 insufficiency increases the risk of thoracic aortic aneurysm and dissection"],"prefix":"10.1093","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1109-3148","authenticated-orcid":false,"given":"Wenyu","family":"Song","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery, Zhongshan Hospital, Fudan University , Fenglin Road 180, Shanghai 200032 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