Shionone attenuates endoplasmic reticulum stress-associated ferroptosis in cardiomyocytes by reducing LCN2 and regulating PI3K/Akt signaling

Ischemia/reperfusion-induced myocardial dysfunction remains a clinical problem and is associated to poor outcomes in patients with cardiovascular disorders, such as myocardial infarction. Shionone is a triterpenoid extracted from the herbal medicine Radix Asteris which has health benefits. This study aimed to explore the roles and functional mechanism of Shionone in regulating myocardial ischemia/reperfusion injury. The network pharmacology was performed to analyze the potential pathway interacted with Shionone in myocardial ischemia/reperfusion injury. The oxygen-glucose deprivation and reperfusion (OGD/R)-treated H9c2 cardiomyocytes and ischemia/reperfusion-induced murine models were regarded as in vitro and in vivo models. Lactate Dehydrogenase (LDH), Reactive Oxygen Species (ROS), glutathione (GSH) and iron levels were analyzed using specific kits. Related protein levels were detected by immunofluorescence staining and western blotting assays. Heart infarct in mice was investigated via TTC staining. Network pharmacology predicted LCN2 and PI3K/Akt signaling might be required by Shionone to involve in myocardial ischemia/reperfusion injury. Shionone mitigated OGD/R-induced Ferroptosis through decreasing LDH release, ROS generation, iron and ACSL4 levels, and enhancing GSH, SLC7A11 an GPX4 levels in cardiomyocytes. Shionone attenuated OGD/R-induced endoplasmic reticulum stress through reducing CHOP, GRP-78, and phosphorylation levels of PERK and eIF2α. Endoplasmic reticulum stress inducer reversed the effects of Shionone on cardiomyocyte Ferroptosis. Shionone decreased LCN2 expression and enhanced activation of PI3K/Akt signaling. Overexpressed LCN2 reversed the effects of Shionone on cardiomyocyte Ferroptosis and endoplasmic reticulum stress in OGD/R-treated cardiomyocytes, and this function was mitigated via PI3K/Akt signaling activation. Shionone mitigated ischemia/reperfusion damage in murine heart by reducing heart infarct. Shionone attenuated endoplasmic reticulum stress-associated Ferroptosis in cardiomyocytes through decreasing LCN2 and activating PI3K/Akt signaling, offering a basis for understanding the potentially cardioprotective potential of Shionone post ischemia/reperfusion injury.

Endoplasmic reticulum stress; Ferroptosis; LCN2; Myocardial ischemia/Reperfusion injury; Shionone.