2. Academic Validation
  3. Targeting USP21 to inhibit abdominal aortic aneurysm progression by suppressing the phenotypic transition of vascular smooth muscle cells

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

  • Cell Rep Med. 2025 Sep 16;6(9):102328. doi: 10.1016/j.xcrm.2025.102328.
Huidan Zhang 1,  Hongwei Yue 1,  Yijun Sun 1,  Guangqi Sun 1,  Kehui Yang 1,  Tangxing Jiang 1,  Sumei Cui 1,  Yang Liu 1,  Yunyun Guo 1,  Wencheng Zhang 2,  Cheng Zhang 2,  Yuguo Chen 3,  Feng Xu 4
Affiliations

Affiliations

  • 1 Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan 250012, China; Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine, China's Ministry of Education, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan 250012, China; National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 2 National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 3 Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan 250012, China; Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine, China's Ministry of Education, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan 250012, China; National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: chen919085@sdu.edu.cn.
  • 4 Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan 250012, China; Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine, China's Ministry of Education, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan 250012, China; National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: xufengsdu@126.com.
PMID: 40925375 DOI: 10.1016/j.xcrm.2025.102328
Abstract

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 ALDH2E506K mutant mice. Our findings highlight USP21 as a critical regulator in AAA pathogenesis and a potential therapeutic target.

Keywords

USP21; VSMC phenotypic switch; abdominal aortic aneurysm; aldehyde dehydrogenase 2; deubiquitinating enzymes.

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