2. Academic Validation
  3. OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C/EBPβ

OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C/EBPβ

  • Acta Pharmacol Sin. 2025 May 7. doi: 10.1038/s41401-025-01566-y.
Ling-Yu She # 1 2 3,  Lu-Yao Li # 1,  Hao Tang # 1 3,  Qin Yu 1,  Feng-Yi Gao 1,  Yu-Qing Zeng 1 2,  Lin-Jie Chen 1 2,  Li Xiong 3,  Li-Wei Li 3,  Fan Chen 1 3,  Jin-Feng Sun 1 4,  Wen-Hua Zheng 5,  Xia Zhao 6 7 8,  Guang Liang 9 10 11
Affiliations

Affiliations

  • 1 The First People's Hospital of Lin'an District, Affiliated Lin'an People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
  • 2 Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
  • 3 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, China.
  • 4 Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji, 133002, China.
  • 5 Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, 999078, China.
  • 6 The First People's Hospital of Lin'an District, Affiliated Lin'an People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. xiazhao@hmc.edu.cn.
  • 7 Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. xiazhao@hmc.edu.cn.
  • 8 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, China. xiazhao@hmc.edu.cn.
  • 9 The First People's Hospital of Lin'an District, Affiliated Lin'an People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. wzmcliangguang@163.com.
  • 10 Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. wzmcliangguang@163.com.
  • 11 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, China. wzmcliangguang@163.com.
  • # Contributed equally.
PMID: 40335710 DOI: 10.1038/s41401-025-01566-y
Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Microglia-mediated neuroinflammation is closely associated with AD pathogenesis. Abnormal deubiquitinating enzyme (DUB) expression is associated with neuroinflammation. Identification of functional DUBs in microglia may provide novel targets for AD treatment. Here, we found that the levels of DUB, ovarian tumor Deubiquitinase 1 (OTUD1), were upregulated in AD model mice and amyloid-beta-induced microglia. OTUD1 knockdown in microglia significantly inhibited neuroinflammation, thereby improving cognitive impairment in AD model mice. Liquid chromatography-tandem mass spectrometry analysis coupled with co-immunoprecipitation revealed the CCAAT/enhancer-binding protein β (C/EBPβ), a key transcription factor regulating microglial inflammation, as an OTUD1-interacting protein. Mechanistically, OTUD1 bound to C/EBPβ and maintained its stability by removing the K48 ubiquitin chain at K253 of C/EBPβ, thereby activating the C/EBPβ-nuclear factor-κB-mediated inflammatory responses in microglia. Overall, our results revealed the roles of the OTUD1-C/EBPβ axis in mediating the microglial inflammatory responses and AD pathology, facilitating the development of new strategies targeting microglial neuroinflammation for AD treatment.

Keywords

Alzheimer’s disease; C/EBPβ; OTUD1; microglia; neuroinflammation.

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