Jiashun Xu,1,* Zongyue Wang,1,* Huifang Wei,1,* Liqin Wang,1 Yun Hong,1 Wenqing Xu,2 Meifen Ding,1 Zheming Song1 

1Department of Anesthesiology, No. 905 Hospital of People’s Liberation Army Navy, Shanghai, 200050, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Shanghai Changzheng Hospital, Shanghai, 200003, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Zheming Song, Department of Anesthesiology, No. 905 Hospital of People’s Liberation Army Navy, No. 1328 Huashan Road, Changning District, Shanghai, 200050, People’s Republic of China, Email nav905hospitalmzk@163.com

Background and Objective: Myocardial ischemia-reperfusion (I/R) injury remains a significant challenge in the treatment of acute myocardial infarction, highlighting the urgent need for effective cardioprotective strategies. Sevoflurane (Sev), a widely used anesthetic, has demonstrated notable cardioprotective potential. This study investigated whether Sev mitigates ferroptosis in myocardial cells by inhibiting the USP7-mediated PTEN/PI3K/AKT pathway.
Methods: Rat myocardial I/R injury and H9c2 cell hypoxia/reoxygenation (H/R) injury models were established. Myocardial injury was assessed through cTnT levels, hemodynamic parameters, and histological analyses. Cell viability, LDH release, TUNEL staining, and ferroptosis markers (GSH, MDA, Fe²+, ROS) were evaluated. Co-IP and CHX assays were employed to explore USP7’s regulation of PTEN stability.
Results: Sev significantly reduced serum cTnT levels, improved hemodynamic function, decreased infarct size, and alleviated myocardial fibrosis and inflammation in rats subjected to I/R injury. In H9c2 cells, Sev enhanced cell viability and suppressed apoptosis. Sev reversed hypoxia/reoxygenation (H/R)-induced USP7 overexpression and ferroptosis, whereas USP7 overexpression attenuated Sev’s protective effects.
Conclusion: Sev protected against myocardial I/R injury by inhibiting USP7, destabilizing PTEN, activating the PI3K/AKT pathway, and suppressing ferroptosis. These findings elucidated the molecular mechanism of Sev’s cardioprotective effect and suggested USP7 as a potential therapeutic target for myocardial protection.

Keywords: sevoflurane, USP7, ferroptosis, ischemia, PTEN