Identification of USP21 as a Novel Regulator of Abdominal Aortic Aneurysm Pathogenesis by Promoting the Pathological Phenotypic Transition of Vascular Smooth Muscle Cell

Abdominal aortic aneurysm (AAA) is a life-threatening vascular condition with no effective cure. This study investigates the role of deubiquitinating enzyme USP21 in AAA development. Through proteomic analysis, we identified USP21 as significantly upregulated in murine and human abdominal aortic tissues. Utilizing USP21 global knockout with Ang II-infused or porcine pancreatic elastase (PPE) induced models, as well as vascular smooth muscle cell (VSMCs)-specific models, we assessed its impact on AAA. Co-immunoprecipitation combined with mass spectrometry revealed downstream targets of USP21. Notably, USP21 exacerbates AAA by deubiquitinating and stabilizing ALDH2 and facilitating the dedifferentiation and phenotypic changes in VSMCs. Pharmacological inhibition of USP21 with disulfiram demonstrated potential therapeutic effects against AAA progression, with efficacy reduced in ALDH2E506K mutant mice. Overall, our findings underscore USP21 as a critical regulator in AAA pathogenesis and highlight its potential as a therapeutic target.