Qihuang Zhuyu Formula Attenuates Myocardial Ischemia ReperfusionInjury by Regulating Autophagy via the NF-κB P65/TRAIL Pathway

INTRODUCTION: Myocardial Ischemia Reperfusion Injury (MIRI) contributes to adverse cardiovascular outcomes. Dysregulated myocardial autophagy plays a key role in MIRI, yet therapeutic strategies targeting this process are limited. Qihuang Zhuyu Formula (QHZYF), a traditional Chinese herbal compound, exhibits cardiovascular protective effects, but its molecular mechanism in MIRI remains unclear. The NF-κB P65/TRAIL signaling axis regulates autophagy in MIRI and may serve as a critical target for QHZYF intervention. METHODS: QHZYF components were analyzed using UPLC-Q-TOF-MS. Network pharmacology identified the NF-κB P65/TRAIL pathway as a core mechanism. In vivo, a rat MIRI model was treated with QHZYF; myocardial injury was assessed via histology, electrocardiography, echocardiography, immunohistochemistry, western blot, and RT-qPCR. In vitro, H9C2 cells underwent hypoxia/reoxygenation and were treated with QHZYF. Autophagy and pathway-related markers, including NF-κB p65, TRAIL, Beclin 1, LC3, and P62, were measured. RESULTS: Network pharmacology and experimental results confirmed that QHZYF targets NF-κB P65/TRAIL to restore myocardial autophagic homeostasis. Treatment reduced cardiomyocyte injury and normalized autophagy markers in both in vivo and in vitro models. DISCUSSION: This study demonstrates that QHZYF exerts cardioprotective effects against MIRI by regulating autophagy and suppressing NF-κB P65/TRAIL signaling. Integration of compound analysis and experimental models revealed the pathway's key role in autophagic imbalance and myocardial injury. QHZYF intervention restored autophagic homeostasis and mitigated cardiomyocyte damage, highlighting its potential application for MIRI prevention and therapy. CONCLUSION: QHZYF alleviates myocardial autophagy imbalance via the NF-κB P65/TRAIL pathway, providing mechanistic insight into its therapeutic potential in MIRI management.