The deubiquitinase OTUD1 stabilizes NRF2 to alleviate hepatic ischemia/reperfusion injury.

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.