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While continuous stress drives vascular smooth muscle cell (VSMC) apoptosis via mitochondrial dysfunction, the precise upstream orchestrators linking these stress signals to the mitochondrial apoptotic cascade remain elusive. By integrating clinical observations and single\u2010cell RNA sequencing, we found that Nuclear Protein 1 (Nupr1), a critical stress\u2010responsive factor, is significantly upregulated in aortas from AD patients and murine models, with enrichment in VSMCs. Remarkably, VSMC\u2010specific Nupr1 deficiency significantly ameliorated AD progression in vivo. Mechanistically, Nupr1 undergoes massive mitochondrial accumulation in Ang II\u2010induced apoptotic VSMCs. Rather than operating as a conventional transcriptional regulator, mitochondrially enriched Nupr1 functions as a pathological spatial switch. It sequesters p53 within mitochondria, driving transcription\u2010independent apoptosis while simultaneously blunting the protective Gadd45b\u2010mediated survival program. Furthermore, in vivo Gadd45b overexpression was sufficient to rescue mitochondrial dysfunction and ameliorate vascular collapse. Taken together, our findings conceptualize the Nupr1\u2010p53\u2010Gadd45b axis as an important determinant of VSMC fate and provide a novel and promising therapeutic strategy for preventing AD progression.<\/jats:p>","DOI":"10.1002\/advs.78143","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T04:33:52Z","timestamp":1792125232000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Nupr1\u2010Mediated p53 Mitochondrial Sequestration Alleviates Aortic Dissection by Restoring the Gadd45b\u2010Dependent Survival Program"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5814-8708","authenticated-orcid":false,"given":"Xi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery Fujian Medical University Union Hospital Fuzhou China"},{"name":"Key Laboratory of Cardio\u2010Thoracic Surgery (Fujian Medical University) 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