USP14 Promotes the Progression of Abdominal Aortic Aneurysm in Mice by Mediating FZD8 Deubiquitination and Activating the Wnt/β-catenin Signaling Pathway

doi:10.3870/j.issn.1672-0741.25.08.022

Abstract

Abstract: Objective To investigate the role of ubiquitin-specific peptidase 14(USP14)-mediated deubiquitination of frizzled 8(FZD8)in activating the Wnt/β-catenin pathway and its impact on abdominal aortic aneurysm(AAA)progression in mice. Methods AAA was induced by subcutaneous implantation of AngⅡ osmotic minipumps.Mice were divided into six groups:control,AAA,USP14 negative control(si-NC),USP14 knockdown(si-USP14),empty-vector control(si-USP14+Ad-GFP),and FZD8 overexpression(si-USP14+Ad-FZD8).Aortic morphology was evaluated by hematoxylin and eosin(HE)staining and verhoeff-van gieson(EVG)staining.Vascular smooth muscle cell apoptosis was detected by TUNEL assay.IL-6 and TNF-α levels were measured by ELISA.Protein expression of USP14,FZD8,Wnt3a and β-catenin was assessed by Western blotting.Co-immunoprecipitation and glutathione s-transferase(GST)pull-down assays were used to examine the interaction between USP14 and FZD8.Ubiquitination assays were performed to evaluate FZD8 deubiquitination. Results Compared with controls,AAA mice exhibited markedly elevated USP14 expression,increased aortic diameter and mass ratio,inflammatory infiltration,and severe elastic fiber fragmentation.Knockdown of USP14 significantly alleviated these pathological changes(all P<0.01).Mechanistically,USP14 directly bound to FZD8 and stabilized it via deubiquitination,thereby sustaining Wnt/β-catenin signaling.Knockdown of USP14 increased FZD8 ubiquitination,downregulated Wnt3a and β-catenin protein levels,markedly reduced aortic diameter,and decreased apoptosis as well as IL-6 and TNF-α expression(all P<0.01). Conclusion USP14 promotes AAA development by deubiquitinating FZD8 and activating the Wnt/β-catenin pathway,indicating that USP14-FZD8 axis may serve as a potential therapeutic target for AAA.

Key words: abdominal aortic aneurysm, ubiquitin-specific peptidase 14, frizzled 8, deubiquitination, Wnt/β-catenin

CLC Number:

R543.16

Wang Hu, Zhao Jing, Zhang Shuo et al. USP14 Promotes the Progression of Abdominal Aortic Aneurysm in Mice by Mediating FZD8 Deubiquitination and Activating the Wnt/β-catenin Signaling Pathway[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(3): 387-392.

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