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Knockdown of USP22 alleviates LPS-induced microglial inflammation and mouse depressive-like behaviors via KAT2A

Neuropsychopharmacology (2025)Cite this article

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Abstract

Depression is a chronic mental illness that has emerged as the second most prevalent disease globally, characterized by symptoms such as low mood, reduced interest, and cognitive impairment. The onset of depression has been associated with microglial inflammation, but the molecular mechanisms behind this are not well understood. Here, we investigated the mechanisms involved in the roles of microglial inflammation in promoting depression by establishing a mouse model of inflammation-related depression via lipopolysaccharide (LPS) administration. We found that LPS treatment led to microglial activation and increased the deubiquitinating enzyme, USP22, expression in the mouse hippocampus. Further, knockdown of USP22 in microglia inhibited depressive-like behaviors and intracerebral inflammation in the mouse model. Moreover, subsequent mechanistic analyses revealed that KAT2A, which serves as a ubiquitination substrate, is modulated by USP22, thereby influencing mitochondrial damage and oxidative stress in microglia. Our findings indicate that USP22 facilitates oxidative stress and inflammatory responses in microglia through the deubiquitination of KAT2A, providing a promising target for the development of therapeutic strategy for the depression treatment.

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Fig. 1: Ubiquitination protein USP22 was upregulated in the hippocampus of LPS induced-depressive mice.
Fig. 2: Knockdown of USP22 in microglia inhibited depressive-like behaviors and inflammation.
Fig. 3: Inhibition of KAT2A repressed LPS-induced microglia inflammation.
Fig. 4: Knockdown of USP22 inhibited KAT2A expression by K48-linked ubiquitination.
Fig. 5: Knockdown of USP22 improved microglia mitochondrial injury via KAT2A.

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All data generated or analysed during this study are included in this manuscript and supplementary material.

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Funding

This study was supported by the National Natural Science Foundation of China (82301357; 82371278).

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Authors and Affiliations

  1. Department of Anesthesiology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China

    Yan Lu, Yuhan Zheng, Xiaoru Sun, Yujie Song, Yilu Zhou, Fuyi Shen & Zhendong Xu

  2. Clinical Research Center, Nantong Research Institute of Traditional Chinese Medicine, Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, Nantong, 226001, China

    Rongrong Huang

  3. Deparment of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, China

    Rongrong Huang

  4. Institute of Applied Public Health, School of Public Health, Nantong University, Nantong, 226019, China

    Rongrong Huang

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  1. Yan Lu
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Contributions

Yan Lu and Rongrong Huang performed the experiments. Yan Lu, Yuhan Zheng, Xiaoru Sun, Yujie Song, Yilu Zhou and Fuyi Shen conducted formal analysis and data curation. Yan Lu and Yuhan Zheng wrote the manuscript. Rongrong Huang and Zhendong Xu administrated this project. All authors have read and agreed to the published version of the paper.

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Correspondence to Rongrong Huang or Zhendong Xu.

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Lu, Y., Zheng, Y., Sun, X. et al. Knockdown of USP22 alleviates LPS-induced microglial inflammation and mouse depressive-like behaviors via KAT2A. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02207-y

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