Background As aortic aneurysms (AAs) enlarge, they can become life-threatening if left undiagnosed or neglected. At present, there is a lack of radical treatments for preventing disease progression. Therefore, we aimed to identify effective drug targets that slow the progression of AAs. Methods A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets which are associated with AAs. Summary statistics for AAs were obtained from two datasets: the UK Biobank (2228 cases and 408,565 controls) and the FinnGen study (3658 cases and 244,907 controls). Cis-expression quantitative trait loci (cis-eQTL) for druggable genes were retrieved from the eQTLGen Consortium and used as genetic instrumental var-iables. Colocalization analysis was performed to determine the probability that single nucleotide polymorphisms (SNPs) associated with AAs and eQTL shared causal genetic variants. Findings Four drug targets (BTN3A1, FASN, PLAU, and PSMA(4)) showed significant MR results in two independent datasets. Proteasome 20S subunit alpha 4 (PSMA(4)) and plasminogen activator, urokinase (PLAU) in particular, were found to have strong evidence for colocalization with AAs, and abdominal aortic aneurysm in particular. Additionally, except for the association between PSMA(4) and intracranial aneurysms, no association between genetically proxied inhibition of PLAU and PSMA(4) was detected in increasing the risk of other cardiometabolic risks and diseases. Interpretation This study supports that drug-targeting PLAU and PSMA(4) inhibition may reduce the risk of AAs. Funding This work was supported by National Key R & D Program of China (NO. 2017YFC0909400), Nature Science Foundation of China (No. 91839302, 81790624), Project supported by Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01), and Tongji Hospital Clinical Research Flagship Program (no. 2019CR207). Copyright (c) 2022 The Authors. Published by Elsevier B.V.