<p>Abdominal aortic aneurysm (AAA) progression is closely linked to inflammation and endothelial dysfunction. Our previous study has demonstrated that increased CD95 ligand (CD95L) and its downstream effector Caspase-8 in the aortic tissue, contributed to AAA by modulating inflammation. However, how the CD95L/Caspase-8 modulated aneurysmal inflammation remains poorly understood. This study investigates how CD95L/Caspase-8 signaling drives endothelial pyroptosis to exacerbate AAA. Using a CaCl₂-induced AAA murine model and primary mouse aortic endothelial cells (MAECs), we demonstrate that CD95L triggers endothelial pyroptosis, characterized by NLRP3 inflammasome activation, Gasdermin D N-terminal (GSDMD-N) cleavage, and Caspase-8/Caspase 1 activation. Electron microscopy confirmed pyroptotic morphology, while flow cytometry excluded apoptosis or necrosis. CD95L elevated IL-1β/IL-18 secretion, which was abolished by Caspase-8 siRNA or inhibitor Z-IETD-FMK. Mechanistically, CD95L suppressed Caspase-8 phosphorylation at Tyr380, enabling its activation of GSDMD-dependent pyroptosis. In vivo, CaCl₂-induced AAA mice exhibited aortic dilation, elastin degradation, and endothelial-specific pyroptosis, all attenuated by endothelial-targeted Caspase-8 knockdown via AAV9-shRNA. This intervention reduced NLRP3 and GSDMD-N expression while preserving vascular integrity. Similarly, SRC kinase activation mitigated pyroptosis markers and aortic damage. These findings establish CD95L as a key mediator of endothelial pyroptosis in AAA via Caspase-8 dephosphorylation and NLRP3/GSDMD-N activation. Targeting Caspase-8 or enhancing SRC activity represents a promising therapeutic strategy to curb AAA progression by preserving endothelial homeostasis.</p>