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

Huidan Zhang; Hongwei Yue; Yijun Sun; Guangqi Sun; Kehui Yang; Tangxing Jiang; Sumei Cui; Yang Liu; Yunyun Guo; Wencheng Zhang; Cheng Zhang; Yuguo Chen; Feng Xu

doi:10.1016/j.xcrm.2025.102328

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. Epub 2025 Sep 8.

Authors

Huidan Zhang¹, Hongwei Yue¹, Yijun Sun¹, Guangqi Sun¹, Kehui Yang¹, Tangxing Jiang¹, Sumei Cui¹, Yang Liu¹, Yunyun Guo¹, Wencheng Zhang², Cheng Zhang², Yuguo Chen³, Feng Xu⁴

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.

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 ALDH2^E506K 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.

MeSH terms

Aldehyde Dehydrogenase, Mitochondrial / genetics
Aldehyde Dehydrogenase, Mitochondrial / metabolism
Angiotensin II
Animals
Aortic Aneurysm, Abdominal* / drug therapy
Aortic Aneurysm, Abdominal* / genetics
Aortic Aneurysm, Abdominal* / metabolism
Aortic Aneurysm, Abdominal* / pathology
Disease Models, Animal
Disease Progression
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular* / metabolism
Muscle, Smooth, Vascular* / pathology
Myocytes, Smooth Muscle* / drug effects
Myocytes, Smooth Muscle* / metabolism
Myocytes, Smooth Muscle* / pathology
Phenotype
Ubiquitin Thiolesterase* / antagonists & inhibitors
Ubiquitin Thiolesterase* / genetics
Ubiquitin Thiolesterase* / metabolism

Substances

Ubiquitin Thiolesterase
Angiotensin II
Aldehyde Dehydrogenase, Mitochondrial