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Plaque instability is a critical determinant of MACE, as fissure formation or rupture of vulnerable plaques can precipitate thromboembolic complications. In this study, we investigate a noncanonical role of proprotein convertase subtilisin\/kexin type 9 (PCSK9) beyond its lipid regulatory function, focusing on its impact on vascular smooth muscle cells (VSMCs) in the context of plaque instability. Our results demonstrate that PCSK9 overactivity markedly promotes ferroptotic cell death in VSMCs, thereby exacerbating plaque vulnerability. Furthermore, we delineate the underlying mechanism: PCSK9 physically interacts with Yes-associated protein 1 and targets it for lysosomal degradation, which, in turn, suppresses the expression of nuclear protein 1. In conclusion, our findings unveil a novel role of PCSK9 in promoting plaque instability by driving ferroptosis in VSMCs, suggesting that targeting PCSK9 presents a potential avenue for plaque stabilization, thereby mitigating the incidence of major MACE.<\/jats:p>","DOI":"10.34133\/research.0922","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T09:19:41Z","timestamp":1757927981000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":9,"title":["PCSK9 Promotes Atherosclerotic Plaque Instability by Inducing VSMC Ferroptosis through the YAP1\u2013NUPR1 Axis"],"prefix":"10.34133","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8191-7950","authenticated-orcid":false,"given":"Yuting","family":"Cui","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan Intern Scientific and Technological Cooperation Base of Arteriosclerotic Disease, School of Basic Medical Sciences, Hengyang Medical School, \rUniversity of South China, Hengyang 421001, Hunan, China."},{"name":"Department of Pathophysiology, School of Medicine, \rSun Yat-sen University, Shenzhen 518107, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5534-0083","authenticated-orcid":false,"given":"Yanyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan Intern Scientific and Technological Cooperation Base of Arteriosclerotic Disease, School of Basic Medical Sciences, Hengyang Medical School, \rUniversity of South China, Hengyang 421001, Hunan, China."},{"name":"Department of Cardiovascular Medicine, the Second Affiliated Hospital, \rUniversity of South China, Hengyang 421001, Hunan, 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