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

Changzhou Cai, Huailu Ma, Jin Peng, Xiang Shen, Xinghua Zhen, Chaohui Yu, Pumin Zhang (), Feng Ji () and Jiewei Wang ()
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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
Feng Ji: The First Affiliated Hospital of Zhejiang University School of Medicine
Jiewei Wang: The First Affiliated Hospital of Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39412-6

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