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USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice

Author

Listed:
  • Changzhou Cai

    (The First Affiliated Hospital of Zhejiang University School of Medicine)

  • Huailu Ma

    (Zhejiang University School of Medicine)

  • Jin Peng

    (The First Affiliated Hospital of Zhejiang University School of Medicine)

  • Xiang Shen

    (Chaser Therapeutics, Inc.)

  • Xinghua Zhen

    (The First Affiliated Hospital of Zhejiang University School of Medicine)

  • Chaohui Yu

    (The First Affiliated Hospital of Zhejiang University School of Medicine)

  • Pumin Zhang

    (Zhejiang University School of Medicine
    The First Affiliated Hospital of Zhejiang University School of Medicine
    Zhejiang University)

  • Feng Ji

    (The First Affiliated Hospital of Zhejiang University School of Medicine)

  • Jiewei Wang

    (The First Affiliated Hospital of Zhejiang University School of Medicine)

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor responsible for mounting an anti-oxidation gene expression program to counter oxidative stress. Under unstressed conditions, Kelch-like ECH-associated protein 1 (KEAP1), an adaptor protein for CUL3 E3 ubiquitin ligase, mediates NRF2 ubiquitination and degradation. We show here that the deubiquitinase USP25 directly binds to KEAP1 and prevents KEAP1’s own ubiquitination and degradation. In the absence of Usp25 or if the DUB is inhibited, KEAP1 is downregulated and NRF2 is stabilized, allowing the cells to respond to oxidative stress more readily. In acetaminophen (APAP) overdose-induced oxidative liver damage in male mice, the inactivation of Usp25, either genetically or pharmacologically, greatly attenuates liver injury and reduces the mortality rates resulted from lethal doses of APAP.

Suggested Citation

  • Changzhou Cai & Huailu Ma & Jin Peng & Xiang Shen & Xinghua Zhen & Chaohui Yu & Pumin Zhang & Feng Ji & Jiewei Wang, 2023. "USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39412-6
    DOI: 10.1038/s41467-023-39412-6
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    References listed on IDEAS

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    1. Yanfeng Liu & Shishi Tao & Lijuan Liao & Yang Li & Hongchang Li & Zhihuan Li & Lilong Lin & Xiaochun Wan & Xiaolu Yang & Liang Chen, 2020. "TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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