The deubiquitinase OTUD1 stabilizes NRF2 to alleviate hepatic ischemia/reperfusion injury
Qi Zhang,
Zihan Chen,
Jinglei Li,
Kunpeng Huang,
Zhihao Ding,
Biao Chen,
Tianxing Ren,
Peng Xu,
Guoliang Wang,
Hongji Zhang,
Xiao-Dong Zhang,
Jinxiang Zhang,
Hui Wang
Affiliations
Qi Zhang
Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, 430068, China
Zihan Chen
Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
Jinglei Li
Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
Kunpeng Huang
Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
Zhihao Ding
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China
Biao Chen
Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
Tianxing Ren
Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
Peng Xu
Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
Guoliang Wang
Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
Hongji Zhang
Department of Surgery, University of Virginia, Charlottesville, VA, 22903, USA
Xiao-Dong Zhang
Hengyang Medical School, University of South China, Hengyang, 421001, China
Jinxiang Zhang
Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Corresponding author. 1277 Jiefang Road, Wuhan, Hubei Province, 430022, China.
Hui Wang
Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Corresponding author. 13 Hangkong Road, Wuhan, Hubei Province, 430022, China.
Hepatic ischemia/reperfusion (I/R) injury is an important cause of liver function impairment following liver surgery. The ubiquitin-proteasome system (UPS) plays a crucial role in protein quality control and has substantial impact on the hepatic I/R process. Although OTU deubiquitinase 1 (OTUD1) is involved in diverse biological processes, its specific functional implications in hepatic I/R are not yet fully understood. This study demonstrates that OTUD1 alleviates oxidative stress, apoptosis, and inflammation induced by hepatic I/R injury. Mechanistically, OTUD1 deubiquitinates and activates nuclear factor erythroid 2-related factor 2 (NRF2) through its catalytic site cysteine 320 residue and ETGE motif, thereby attenuating hepatic I/R injury. Additionally, administration of a short peptide containing the ETGE motif significantly mitigates hepatic I/R injury in mice. Overall, our study elucidates the mechanism and role of OTUD1 in ameliorating hepatic I/R injury, providing a theoretical basis for potential treatment using ETGE-peptide.
