Targeting USP21 to inhibit abdominal aortic aneurysm progression by suppressing the phenotypic transition of vascular smooth muscle cells

Abdominal aortic aneurysm (AAA) is a life-threatening condition lacking effective treatment. We investigate the role of the deubiquitinating enzyme USP21 in AAA development. Proteomic analysis reveals significant upregulation of USP21 in murine and human abdominal aortic tissues. Using USP21 global knockout models induced by angiotensin II or porcine pancreatic elastase (PPE), and vascular smooth muscle cell (VSMC)-specific models, we assess USP21's impact on AAA. Coimmunoprecipitation and mass spectrometry identify downstream targets of USP21. USP21 exacerbates AAA by stabilizing aldehyde dehydrogenase 2 (ALDH2) and promoting VSMC dedifferentiation and phenotypic changes. Pharmacological inhibition of USP21 with disulfiram shows therapeutic potential against AAA progression, with efficacy reduced in ALDH2^E506K mutant mice. Our findings highlight USP21 as a critical regulator in AAA pathogenesis and a potential therapeutic target.