THSD7A Exacerbates Atherosclerosis via Activation of Signaling Axis αvβ3/CEBPD/IL1A

ABSTRACT Our previous genome‐wide screening has linked THSD7A (thrombospondin type 1 domain containing 7A) gene to human coronary artery disease (CAD). How THSD7A contributes to atherosclerosis, however, remains unclear. In this study, we show THSD7A is increased in human carotid arteries and mouse atherosclerotic plaques. In apolipoprotein E knockout ( ApoE −/− ) mice, the overexpression of THSD7A increases monocyte‐endothelial adhesion and macrophage infiltration, exacerbating atherosclerotic lesions, whereas Thsd7A knockout ( Thsd7A −/− ) attenuates these phenotypic changes. Integrated single‐cell and bulk transcriptomic profiles demonstrate that THSD7A activates IL1A (Interleukin 1 alpha) signaling, augmenting endothelial inflammation. Mechanistically, THSD7A binds to integrin αvβ3, and such binding activates ERK (Extracellular signal‐regulated kinase) and augments IL1A ‐associated proinflammatory signaling. Notably, IL1A serves as a transcriptional target of CEBPD (CCAAT/enhancer‐binding protein delta), and CEBPD knockdown rescues THSD7A‐ mediated endothelial inflammation. These findings establish THSD7A as a novel and critical mediator in the regulation of the αvβ3/CEBPD/IL1A axis that controls endothelial inflammatory responses associated with atherosclerosis and demonstrate the importance of CEBPD as a downstream molecule in mediating THSD7A ‐associated signaling. This study positions THSD7A as both a genetic marker and a potential therapeutic target.