Salidroside Attenuates High-Altitude Hypoxic Myocardial Injury Through Modulation of Oxidative Stress and AKT/GSK-3β Signaling Pathways.

Hypoxia-related myocardial injury is characterized by oxidative stress, mitochondrial dysfunction, and apoptosis, ultimately resulting in impaired cardiac structure and function. Salidroside (SAL), a major bioactive component of Rhodiola, has been shown to have antioxidant and cardioprotective effects, but its role in hypoxia-related myocardial injury remains incompletely understood. In this study, we combined network pharmacology, molecular docking, and experimental validation to investigate the protective effect of SAL in CoCl2-induced hypoxia-mimetic models. In vitro, SAL improved cell viability, reduced ROS accumulation, restored mitochondrial membrane potential and ATP production, and attenuated apoptosis in CoCl2-treated H9C2 cells. In vivo, SAL alleviated electrocardiographic abnormalities, myocardial histopathological injury, cardiomyocyte hypertrophy, and associated lung and liver damage in CoCl2-treated rats. Mechanistically, SAL modulated the Akt/GSK-3β signaling axis under CoCl2-induced stress. Notably, Akt inhibition experiments revealed that SAL promotes protective GSK-3β phosphorylation and exerts its anti-apoptotic effects through a largely Akt-independent mechanism. Collectively, these findings indicate that SAL alleviates hypoxia-induced myocardial injury through the attenuation of oxidative stress, the preservation of mitochondrial function, the suppression of apoptosis, and the robust, Akt-independent regulation of GSK-3β.