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Protein phosphatase 2A (PP2A), the most abundant serine\/threonine phosphatase in eukaryotes, is pivotal in regulating intracellular signaling. This study investigates the role of PP2A in the pathogenesis of AAD. Analysis of available datasets revealed that PP2Ac\u03b1 is the most significantly downregulated PP2A subunit in human and mouse aneurysm tissues. Vascular smooth muscle cell (VSMC)\u2010specific PP2Ac\u03b1 knockout exacerbates \u03b2\u2010Aminopropionitrile (BAPN)\u2010induced aortic dissection and elastase\u2010induced abdominal aortic aneurysm in mice. Collagen\u2010based contraction assays, Western blot, and gelatin zymography confirmed that the deficiency of PP2Ac\u03b1 results in decreased contractility, contractile markers, and elevated production of matrix metallopeptidase 2 (MMP2) in VSMCs. Furthermore, PP2Ac\u03b1 deficiency promoted VSMC phenotypic switching through stabilizing Kruppel\u2010like factor 4 (KLF4). Mechanistically, PP2Ac\u03b1 binds to and dephosphorylates protein kinase B 1 (AKT1), thereby reducing phosphorylation of the AKT1 substrate KLF4 at Thr398. The deficiency of PP2Ac\u03b1 diminishes KLF4 phosphorylation\u2010dependent ubiquitination and degradation, leading to the suppression of VSMC contractile gene transcription. The findings underscore a critical role for PP2Ac\u03b1 in regulating VSMC phenotypic switching and AAD progression by controlling KLF4 phosphorylation and ubiquitination, offering novel insights into the molecular pathogenesis underlying AAD.<\/jats:p>","DOI":"10.1002\/advs.202500102","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T20:01:11Z","timestamp":1753732871000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["PP2Ac\u03b1 Deficiency in Vascular Smooth Muscle Cells Accelerates Aortic Aneurysm and Dissection by Regulating KLF4 Phosphorylation and Ubiquitination"],"prefix":"10.1002","volume":"12","author":[{"given":"Wei\u2010Peng","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences Peking University Health Science Center  38 Xueyuan Road, Haidian District Beijing 100191 China"},{"name":"State Key Laboratory 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