biostudies-literatureXu QNatural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)National Natural Science Foundation of China (National Science Foundation of China)291https://www.ebi.ac.uk/biostudies/studies/S-EPMC9203583biostudies-literatureUnknown8(1)Myocardial ischemia/reperfusion (I/R) injury is a complex pathological process that is still not fully understood. The oxidative stress response has a critical role in the occurrence and progression of myocardial ischemia/reperfusion injury. This study investigated the specific mechanism of ubiquitin-specific protease 7 (USP7) regulation of myocardial ischemia/reperfusion injury from the perspective of proteasome degradation and its relation with the Keap1 pathway, a vital regulator of cytoprotective responses to endogenous and exogenous stress induced by reactive oxygen species (ROS) and electrophiles. Our data indicated that USP7 expression is increased during myocardial ischemia/reperfusion injury in mice, while its inhibiting suppressed the generation of oxygen free radicals and myocardial cell apoptosis, reduced myocardial tissue damage, and improved heart function. Mechanistically, USP7 stabilizes Keap1 by regulating its ubiquitination. Taken together, these findings demonstrate the potential therapeutic effect of USP7 on myocardial ischemia/reperfusion injury.Cell death discoveryUbiquitin-specific protease 7 regulates myocardial ischemia/reperfusion injury by stabilizing Keap1.PMC92035832021A151501138782170416Liu XLing SChai RLiu MLuo ZLiu NXu QOu WGu JLiu SJin YfalseUbiquitin-specific protease 7 regulates myocardial ischemia/reperfusion injury by stabilizing Keap1.Myocardial ischemia/reperfusion (I/R) injury is a complex pathological process that is still not fully understood. The oxidative stress response has a critical role in the occurrence and progression of myocardial ischemia/reperfusion injury. This study investigated the specific mechanism of ubiquitin-specific protease 7 (USP7) regulation of myocardial ischemia/reperfusion injury from the perspective of proteasome degradation and its relation with the Keap1 pathway, a vital regulator of cytoprotective responses to endogenous and exogenous stress induced by reactive oxygen species (ROS) and electrophiles. Our data indicated that USP7 expression is increased during myocardial ischemia/reperfusion injury in mice, while its inhibiting suppressed the generation of oxygen free radicals and myocardial cell apoptosis, reduced myocardial tissue damage, and improved heart function. Mechanistically, USP7 stabilizes Keap1 by regulating its ubiquitination. Taken together, these findings demonstrate the potential therapeutic effect of USP7 on myocardial ischemia/reperfusion injury.2022-01-01T00:00:00Z2022 Jun2025-04-04T03:06:15.084Z2025-02-19T05:06:29.061ZS-EPMC92035833571090210.1038/s41420-022-01086-2