USP14介导FZD8去泛素化激活Wnt/β-catenin通路促进小鼠腹主动脉瘤进展*

doi:10.3870/j.issn.1672-0741.25.08.022

华中科技大学学报（医学版） ›› 2026, Vol. 55 ›› Issue (3): 387-392.doi: 10.3870/j.issn.1672-0741.25.08.022

USP14介导FZD8去泛素化激活Wnt/β-catenin通路促进小鼠腹主动脉瘤进展^*

王虎¹, 赵静², 张硕³, 周志远¹, 马涛¹, 李藏妥^1△

¹唐山市工人医院介入科,唐山 063000
华北理工大学附属医院 ²肾内科 ³血管外科,唐山 063000

收稿日期:2025-08-15 出版日期:2026-06-15 发布日期:2026-06-17
通讯作者: ^△E-mail:cangtuoli@163.com
作者简介:王虎,男,1986年生,医学硕士,E-mail:Wh869128@163.com
基金资助:
^*河北省卫生健康委员会医学科研课题计划项目(No.20231254)

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

Wang Hu¹, Zhao Jing², Zhang Shuo³ et al

¹Departmemt of Interventional Radiology, Tangshan Workers’Hospital, Tangshan 063000, China
²Departmemt of Nephrology, ³Departmemt of Vascular Surgery, Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China

Received:2025-08-15 Online:2026-06-15 Published:2026-06-17
Contact: ^△E-mail:cangtuoli@163.com

摘要/Abstract

摘要： 目的探讨泛素-蛋白酶体系统14(ubiquitin-proteasome system14,UPS14)介导卷曲受体8(frizzled 8,FZD8)去泛素化激活Wnt/β-catenin通路对小鼠腹主动脉瘤(abdominal aortic aneurysm,AAA)的影响。方法通过皮下植入AngⅡ渗透性微量泵构建小鼠AAA模型,将小鼠分为对照组,模型(AAA)组,USP14阴性对照(si-NC)组,USP14敲低(si-USP14)组,空载体对照(si-USP14+Ad-GFP)组和FZD8过表达(si-USP14+Ad-FZD8)组。苏木精-伊红(hematoxylin and eosin,HE)染色和弹力纤维-胶原纤维(Verhoeff-van Gieson,EVG)双重染色观察血管形态变化;原位末端标记(TUNEL)染色检测平滑肌细胞凋亡;酶联免疫吸附法测定IL-6、TNF-α含量;蛋白免疫印记检测USP14、FZD8、Wnt3a、β-catenin表达;免疫共沉淀法测定和GST融合蛋白沉降实验测定评估USP14和FZD8之间的相互作用;泛素化实验评价FZD8的去泛素化。结果与对照组比较,AAA组小鼠USP14表达显著升高,主动脉直径、质量比增大,管壁炎性浸润伴弹性蛋白降解;敲低USP14后上述病变明显缓解(均P<0.01)。机制上,USP14通过去泛素化与FZD8直接结合并抑制其降解,维持Wnt/β-catenin信号活性;敲低USP14可升高FZD8泛素化水平,下调Wnt3a及β-catenin蛋白,显著缩小主动脉直径、减少细胞凋亡及IL-6、TNF-α表达(均P<0.01)。结论 USP14通过去泛素化FZD8激活Wnt/β-catenin通路,促进AAA进展。

关键词: 腹主动脉瘤, USP14, FZD8, 去泛素化, Wnt/β-catenin

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

中图分类号:

R543.16

王虎, 赵静, 张硕, 周志远, 马涛, 李藏妥. USP14介导FZD8去泛素化激活Wnt/β-catenin通路促进小鼠腹主动脉瘤进展^*[J]. 华中科技大学学报（医学版）, 2026, 55(3): 387-392.

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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USP14介导FZD8去泛素化激活Wnt/β-catenin通路促进小鼠腹主动脉瘤进展^*

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

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