Sevoflurane Alleviates Cardiomyocyte Ferroptosis via Ubiquitin-Specific Protease 7/Phosphatase and Tensin Homolog Modulation.

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.