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

Acta Pharmacologica Sinica volume 46, pages 2608–2621 (2025)Cite this article

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.

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Fig. 1: OTUD1 is upregulated in different AD model mice and Aβ-induced BV2 cells.
Fig. 2: OTUD1 knockout improves cognitive disfunction and synaptic impairment in Aβ model mice.
Fig. 3: OTUD1 knockdown improves neuroinflammation in Aβ infused mice.
Fig. 4: Microglia OTUD1 knockdown improves cognitive impairment and synaptic function in 3×Tg model mice.
Fig. 5: Microglia OTUD1 inhibition reduces Aβ-induced inflammation and neuronal cell damage.
Fig. 6: OTUD1 directly interacts with C/EBPβ.
Fig. 7: OTUD1 regulates the stability of C/EBPβ.
Fig. 8: OTUD1 regulates the expression of C/EBPβ through deubiquitination.

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Acknowledgements

This study was supported by the Natural Science Foundation of Zhejiang Province (ZCLQN25H3101 to LYS.), National Natural Science Foundation of China (21961142009 to GL), Zhejiang Provincial Key Scientific Project (2021C03041 to GL), and Medical and Health Science and Technology Project of Zhejiang Province (2024KY055 to XZ).

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  1. These authors contributed equally: Ling-yu She, Lu-yao Li, Hao Tang

Authors and Affiliations

  1. The First People’s Hospital of Lin’an District, Affiliated Lin’an People’s Hospital, Hangzhou Medical College, Hangzhou, 310014, China

    Ling-yu She, Lu-yao Li, Hao Tang, Qin Yu, Feng-yi Gao, Yu-qing Zeng, Lin-jie Chen, Fan Chen, Jin-feng Sun, Xia Zhao & Guang Liang

  2. Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014, China

    Ling-yu She, Yu-qing Zeng, Lin-jie Chen, Xia Zhao & Guang Liang

  3. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, China

    Ling-yu She, Hao Tang, Li Xiong, Li-wei Li, Fan Chen, Xia Zhao & Guang Liang

  4. Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji, 133002, China

    Jin-feng Sun

  5. Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, 999078, China

    Wen-hua Zheng

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Contributions

GL and XZ contributed to the literature search and study design. LYS participated in the drafting of the article. LYS, LYL, HT, YQZ, FYG, JFS, LWL, and LX carried out the experiments. FC, QY and LJC contributed to data collection and analysis. WHZ contributes to methodology. GL and XZ revised the manuscript.

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Correspondence to Xia Zhao or Guang Liang.

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She, Ly., Li, Ly., Tang, H. et al. OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer’s disease by deubiquitinating C/EBPβ. Acta Pharmacol Sin 46, 2608–2621 (2025). https://doi.org/10.1038/s41401-025-01566-y

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