Salidroside attenuates myocardial ischemia-reperfusion-induced oxidative stress and ferroptosis by promoting USP11-mediated deubiquitination of PRDX2

Abstract

Myocardial ischemia/reperfusion (I/R) injury is closely associated with excessive oxidative stress and ferroptosis. Salidroside (Sal), a major active component of Rhodiola, has demonstrated cardioprotective properties, yet its precise mechanisms in regulating ferroptosis remain unclear. The present study investigated whether Sal attenuates myocardial I/R injury by modulating ubiquitin-specific protease 11 (USP11)-mediated deubiquitination and stabilization of peroxiredoxin 2 (PRDX2). An in vitro H9c2 anoxia/reoxygenation (A/R) model and an in vivo rat I/R model were established. Sal significantly improved the viability of A/R-injured H9c2 cells and reduced reactive oxygen species accumulation, ferrous iron overload and lipid peroxidation. Mechanistically, Sal upregulated the expression levels of USP11, glutathione peroxidase 4 and PRDX2 while suppressing prostaglandin-endoperoxide synthase 2; notably, these effects were attenuated by USP11 silencing. Molecular docking and cellular thermal shift assay analyses suggested that USP11 may represent a potential molecular target involved in Sal-mediated cardioprotection, thereby increasing its thermal stability and strengthening the USP11-PRDX2 interaction. This may facilitate the USP11-mediated stabilization of PRDX2, prolonging its half-life and preserving cellular redox homeostasis. In vivo experiments further demonstrated that Sal pretreatment markedly reduced myocardial infarct size and improved cardiac contractile function, which was associated with the concurrent upregulation of the USP11-PRDX2 axis. Collectively, these findings indicate that Sal confers robust cardioprotection against I/R injury by engaging USP11 and promoting the stabilization of PRDX2, thereby suppressing oxidative stress and ferroptosis. USP11 represents a promising therapeutic target for mitigating myocardial I/R injury.