CD74 Blockade Disrupts Endothelial Migrasome Signaling to Prevent Inflammatory Macrophage Differentiation and Inhibit Atherosclerotic Progression

Abstract Endothelial dysfunction and abnormal activation of the monocyte‐macrophage system form a critical loop in atherosclerosis. The role of migrasomes in endothelial‐immune 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^−/‐ mouse models and single‐cell multi‐omics data, migrasome activity is mapped using Gene Set Variation Analysis (GSVA) algorithms. Co‐culture systems and anti‐Cluster of differentiation 74 (CD74) blocking experiments are employed to investigate immune‐metabolic 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‐mediated 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‐functional entities – serving both as biomarkers of endothelial stress and molecular drivers of immune microenvironment deterioration. The discovery of the “migrasome‐APP‐CD74” signaling network opens new avenues for developing organelle‐targeted therapies to interrupt the vicious cycle of vascular inflammation.