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Ubiquitination, a critical post-translational modification, regulates diverse macrophage functions, including lipoprotein metabolism, inflammation, oxidative stress, mitophagy, autophagy, efferocytosis, and programmed cell death (pyroptosis, necroptosis, ferroptosis, and apoptosis). This review highlights the regulatory roles of ubiquitination in macrophage-driven CVD progression, focusing on its effects on cholesterol metabolism, inflammation, activation, polarization, and the survival of macrophages. Targeting ubiquitination pathways has therapeutic potential by enhancing macrophage autophagy, reducing inflammation, and improving plaque stability. However, challenges, such as off-target effects, ubiquitination crosstalk, and macrophage heterogeneity, must be addressed. By integrating advances in ubiquitination biology, therapeutic strategies can be developed to mitigate CVD and other macrophage-driven inflammatory diseases. This review underscores the potential of ubiquitination-targeting therapies for mitigating CVD and highlights the key areas for further investigation.<\/jats:p>","DOI":"10.3390\/ijms26094260","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T05:50:17Z","timestamp":1745992217000},"page":"4260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Role of Ubiquitination on Macrophages in Cardiovascular Diseases and Targeted Treatment"],"prefix":"10.3390","volume":"26","author":[{"given":"Li","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"The Research Units of West China (2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"The Research Units of West China (2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"The Research Units of West China (2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronghua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"The Research Units of West China (2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E93","DOI":"10.1161\/CIR.0000000000001123","article-title":"Heart Disease and Stroke Statistics\u20142023 Update: A Report from the American Heart Association","volume":"147","author":"Tsao","year":"2023","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/s41590-018-0113-3","article-title":"Regulation of Macrophage Immunometabolism in Atherosclerosis","volume":"19","author":"Koelwyn","year":"2018","journal-title":"Nat. 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