BACKGROUND: Smoking is a well-established risk factor for abdominal aortic aneurysm (AAA). However, the molecular pathways underlying this relationship remain poorly understood. This study aimed to identify circulating protein mediators that may explain the association between smoking and AAA. METHODS: We conducted a network Mendelian randomization (MR) study utilizing summary-level data from the largest available genome-wide association studies. Our primary smoking exposure was the lifetime smoking index, with smoking initiation and cigarettes per day included as supplementary traits. The AAA dataset comprised 39,221 cases and 1,086,107 controls. Protein data were sourced from two large cohorts: UKB-PPP, where proteins were measured using the Olink platform in 54,219 individuals, and deCODE, where proteins were measured using the SomaScan platform in 35,559 individuals. Two-sample MR was employed to estimate the association between smoking and AAA (β RESULTS: Genetically predicted smoking traits were consistently associated with an increased risk of AAA. The lifetime smoking index was associated with the levels of 543 out of 5,764 unique circulating proteins, with 470 of these associations replicated in supplementary analyses using additional smoking traits and protein sources. Among the smoking-related proteins, genetically predicted levels of 22 were associated with AAA risk. Eight mediation pathways were identified accounting for 42.7% of the total smoking-AAA association and with mediation effects >
4% for ADAMTS15, IL1RN, MMP12, PGF, PCSK9, and UXS1. CONCLUSION: This study identified numerous circulating proteins potentially causally linked to smoking, and eight of these proteins were found to mediate the association between smoking and AAA risk.