Huanglian Jiedu Decoction Alleviates Myocardial Ischemia-Reperfusion Injury via AKT-Mediated Regulation of Endoplasmic Reticulum Stress

Purpose: Modulation of the AKT signaling pathway can effectively regulate endoplasmic reticulum stress (ERS) and inhibit ischemia-induced cardiomyocyte apoptosis in myocardial ischemia-reperfusion injury (MIRI). The present study was designed to investigate the role of AKT and ERS in the modulation of MIRI by Huanglian Jiedu Decoction (HLJDD) through in vitro and in vivo experiments.Methods: In vivo studies employed a rat model of MIRI with three HLJDD dosage groups and a nicorandil control group. Comprehensive evaluations were conducted, including assessments of cardiac function, histopathological analysis, apoptosis detection, and immunohistochemical examination of ERS markers. For in vitro validation, H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation conditions, and cellular viability assays were combined with ultrastructural and molecular analyses. Investigations guided by network pharmacology focused on the PERK/eIF2α/CHOP signaling pathway and AKT phosphorylation.Results: HLJDD demonstrated dose-dependent cardioprotective effects through attenuation of myocardial apoptosis and ERS activation. Mechanistic studies revealed its ability to restore AKT phosphorylation and suppress the PERK/eIF2α/CHOP signaling cascade. The cardioprotective effects were abolished upon AKT inhibition, thereby confirming the specificity of this pathway.Conclusion: HLJDD may serve as a potential therapeutic candidate for ischemia-induced cardiomyocyte apoptosis during MIRI. HLJDD exerts its effects by inhibiting the AKT-mediated PERK/eIF2α/CHOP signaling pathway, attenuating ERS and thereby reducing MIRI-induced apoptosis.