2. Academic Validation
  3. USP25 regulates atherosclerosis by restricting RIPK1-mediated inflammatory responses

USP25 regulates atherosclerosis by restricting RIPK1-mediated inflammatory responses

  • EBioMedicine. 2026 Apr:126:106213. doi: 10.1016/j.ebiom.2026.106213.
Xian Su 1,  Bincheng Zhou 2,  Yanqi Xu 2,  Xue Du 2,  Jiaqing Chen 2,  Maojin Yin 2,  Xiaomin Miao 3,  Ying Zhao 4,  Deqi Wang 5,  Zhenhu Zhu 2,  Zhongding Li 2,  Fang Cai 6,  Wei Wang 7,  Gaojun Wu 8,  Jingyong Huang 9,  Weihong Song 10,  Xu Wang 11
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), 325000, Wenzhou, China; Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325015, Wenzhou, China.
  • 2 School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), 325000, Wenzhou, China.
  • 3 Department of Pharmacy, The Second People's Hospital of Xiaoshan District, 311241, Hangzhou, China.
  • 4 School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China.
  • 5 The First School of Medicine and School of Information and Engineering, Wenzhou Medical University, 325035, Wenzhou, China.
  • 6 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), 325000, Wenzhou, China.
  • 7 Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, 310019, Hangzhou, China.
  • 8 Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China.
  • 9 Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325015, Wenzhou, China. Electronic address: [email protected].
  • 10 Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research for Mental Disorders, Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, 325035, Wenzhou, China. Electronic address: [email protected].
  • 11 School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), 325000, Wenzhou, China. Electronic address: [email protected].
PMID: 41861519 DOI: 10.1016/j.ebiom.2026.106213
Abstract

Background: Atherosclerosis is a common vascular disease that poses a serious threat to global health. However, the mechanism underlying the pathogenesis and progression of atherosclerosis remains elusive.

Methods: We analysed the expression of deubiquitinating Enzymes in human atherosclerotic lesions and found that USP25 was significantly downregulated. The role of USP25 in atherosclerosis was validated in mouse models with an apoE-/- background. The protein substrates of USP25 were identified by mass spectrometry. Various biochemical methods were adopted to study the role of USP25 in signal transduction.

Findings: USP25 was predominantly expressed in macrophages in atherosclerotic lesions, and ablation of macrophagic USP25 significantly exacerbated atherosclerosis in apoE-/- mice accompanied by increased lipid deposition, macrophage infiltration, and vascular inflammation. Upon stimulation with ox-LDL or TNF-α, USP25 inhibited inflammatory responses in macrophages by restricting the NF-κB pathway. Mass spectrometry analysis identified RIPK1 as a USP25 substrate. Mechanistically, USP25 physically interacted with RIPK1 and removed K63 ubiquitin chains from RIPK1 via the C178 active site, thereby attenuating RIPK1-mediated signal transduction.

Interpretation: This study elucidated the function and molecular mechanism of USP25 in atherosclerosis, identifying USP25 as a beneficial regulator for this disease.

Funding: This work was supported by the Natural Science Foundation of Zhejiang Province (LZ24H090003 to X.W. and LTGY23H090001 to W.W.), the National Natural Science Foundation of China (82150710557 and 82293642 to W.S.; 81971143 to X.W., and 82271347 to G.W.), and Wenzhou Municipal Science and Technology Bureau (Y2021094 to J.H.).

Keywords

Atherosclerosis; Inflammation; RIPK1; USP25; Ubiquitination.

Figures
Products
Inhibitors & Agonists