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The role of migrasomes in endothelial\u2010immune interactions remains unclear. This study explores migrasome evolution in the atherosclerotic (AS) microenvironment, highlighting their function as amplifiers in the inflammatory cascade. Through analysis of ApoE<jats:sup>\u2212\/\u2010<\/jats:sup> mouse models and single\u2010cell multi\u2010omics data, migrasome activity is mapped using Gene Set Variation Analysis (GSVA) algorithms. Co\u2010culture systems and anti\u2010Cluster of differentiation 74 (CD74) blocking experiments are employed to investigate immune\u2010metabolic reprogramming triggered by migrasome cargo signaling. Advanced imaging and functional studies demonstrated that the interaction between amyloid protein precursor (APP) ligands on endothelial cells and CD74 receptors on macrophages triggers endothelial cells to produce more migrasomes. The clinical relevance of these findings is confirmed through CD74 blocking experiments, which effectively disrupted migrasome\u2010mediated signaling and attenuated atherosclerotic progression. Importantly, migrasome content is positively correlated with the severity of atherosclerosis. These results fundamentally challenge existing paradigms of intercellular communication by establishing migrasomes as dual\u2010functional entities \u2013 serving both as biomarkers of endothelial stress and molecular drivers of immune microenvironment deterioration. The discovery of the \u201cmigrasome\u2010APP\u2010CD74\u201d signaling network opens new avenues for developing organelle\u2010targeted therapies to interrupt the vicious cycle of vascular inflammation.<\/jats:p>","DOI":"10.1002\/advs.202502838","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T10:36:08Z","timestamp":1750674968000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["CD74 Blockade Disrupts Endothelial Migrasome Signaling to Prevent Inflammatory Macrophage Differentiation and Inhibit Atherosclerotic Progression"],"prefix":"10.1002","volume":"12","author":[{"given":"Kangnan","family":"Zhang","sequence":"first","affiliation":[{"name":"Clinical Research Institue Shanghai General Hospital Shanghai Jiao tong University School of Medicine  Shanghai 200080 China"},{"name":"Department of Gastroenterology Tongren Hospital Shanghai Jiao tong University School of Medicine  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