Si-Miao-Yong-An decoction suppresses necroptosis by regulating the p53 pathway in myocardial ischemia/reperfusion injury

Myocardial ischemia/reperfusion (I/R) injury is a serious complication during the recanalization treatment of myocardial infarction (MI), which seriously affects the prognosis of patients. As a renowned traditional Chinese medicinal formulation, Si-Miao-Yong-An decoction (SMYA) has therapeutic effects on myocardial I/R injury, although its underlying mechanisms, particularly concerning regulated cell death pathways, are not fully understood. This study aimed to explore the therapeutic effect and possible mechanism of SMYA in myocardial I/R injury. C57BL/6J mice were divided into sham, model, and SMYA-treated groups (low, medium and high-dose). In this study, we identified 13 main components of SMYA using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Moreover, SMYA improved cardiac dysfunction caused by myocardial I/R injury, decreased the levels of myocardial injury markers, reduced the myocardial infarct size, and alleviated pathological changes in the myocardium. In addition, transcriptomic analysis predicted that the p53 signaling pathway may be a potential target for its function. To this end, the result of western blotting revealed that SMYA inhibited myocardial cell necroptosis by regulating the p53 and RIPK1/RIPK3/MLKL pathways. Overall, SMYA suppressed necroptotic processes induced by myocardial I/R injury, likely mediated by the modulation of the p53 and RIPK1/RIPK3/MLKL pathways. Therefore, SMYA may be a potential therapeutic agent for treating myocardial I/R injury.