Systematic Identification and Functional Validation of CASP10 as a DNA ‐Damage‐Responsive Driver of Endothelial Pyroptosis in Atherosclerosis

ABSTRACT Atherosclerosis (AS) is a chronic inflammatory disease driven by endothelial dysfunction and plaque instability. The DNA damage response (DDR) has been implicated in endothelial cell fate; its precise role in AS remains unclear. This study aims to identify DDR‐related biomarkers associated with AS and elucidate their mechanisms in endothelial pyroptosis. Our analysis identified 66 DDR‐related genes, which achieved over 80% accuracy in discriminating early from advanced lesions and hemorrhagic from non‐hemorrhagic plaques in external datasets, and reached 100% accuracy in differentiating plaque stability. CASP10 emerged as a top diagnostic biomarker (AUC = 0.991) compared to other DDR genes. Single‐cell analysis confirmed elevated CASP10 expression in endothelial cells of AS plaques. Functional experiments revealed that CASP10 is both necessary and sufficient for ox‐LDL‐induced DNA damage and pyroptosis in HUVECs. CASP10 overexpression exacerbated γH 2 AX accumulation, NLRP3 expression, GSDMD‐N cleavage and IL‐1β release, while CASP10 knockdown attenuated these effects. Overall, CASP10 serves as a reliable biomarker for identifying unstable plaques and functions as a pivotal mediator linking DNA damage to endothelial pyroptosis. Targeting CASP10 may represent a novel therapeutic strategy to reduce endothelial cell death and stabilise atherosclerotic plaques.