以USP21为靶点，通过抑制血管平滑肌细胞表型转变抑制腹主动脉瘤进展。

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-09-16 Epub Date: 2025-09-08 DOI:10.1016/j.xcrm.2025.102328

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

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引用次数: 0

摘要

腹主动脉瘤是一种危及生命的疾病，缺乏有效的治疗方法。我们研究了去泛素化酶USP21在AAA发育中的作用。蛋白质组学分析显示，USP21在小鼠和人腹主动脉组织中显著上调。利用血管紧张素II或猪胰腺弹性酶（PPE）诱导的USP21基因敲除模型，以及血管平滑肌细胞（VSMC）特异性模型，我们评估了USP21对AAA的影响。USP21通过稳定醛脱氢酶2 （ALDH2）和促进VSMC去分化和表型改变而加重AAA。双硫仑对USP21的药理抑制显示出对AAA进展的治疗潜力，但在ALDH2E506K突变小鼠中疗效降低。我们的研究结果强调了USP21是AAA发病机制的关键调节因子和潜在的治疗靶点。

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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.

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.