Liquiritin Regulates The SLC7A11/GPX4 Pathwayinhibition Of Cardiotoxicity Of Doxorubicin-induced Ferroptosis In Cardiomyocytes

Objective:Doxorubicin is widely used in cancer treatment,but its cardiotoxicity limits its clinical application.The mechanism of doxorubicin-induced cardiotoxicity is not clear.Ferroptosis is the main regulated form of cell death in DOX cardiotoxicity.Liquiritin(LIQ)is the main component of glycyrrhiza root and has anti-inflammatory,antioxidant,anti-apoptotic,antibacterial,and anticancer effects.However,it is not clear whether it can alleviate the cardiotoxicity induced by Doxorubicin.This project established Doxorubicin(DOX)cardiotoxicity mouse model.To investigate whether liquiritin improves doxorubicin cardiotoxicity and cardiomyocyte injury by inhibiting Ferroptosis of cardiomyocytes and whether it is regulated by SLC7A11/GPX4 axis.To provide an experimental and theoretical basis for improving doxorubicin cardiotoxicity prevention.Method:1.Animal experiment: Doxorubicin hydrochloride lipo solution was injected intraperitoneally at a dose of 15 mg/kg to establish an acute cardiotoxic injury model of C57 mice.The pathological changes of animal body weight,heart weight,and heart tissue were observed.The contents of CK,CTn T,and LDH in the serum of mice were determined by a biochemical kit.C57 mice were randomly divided into 5 groups:normal group(Control group),doxorubicin group(DOX group),doxorubicin group + liquiritin low-dose group(DOX+LIQ L group),doxorubicin group + liquiritin medium-dose group(DOX+LIQ M group),doxorubicin group + liquiritin high-dose group(DOX+LIQ H group).Morphological changes in the myocardium were detected by HE staining.Biochemical kits were used to detect CK and LDH levels.The contents of GSH,GSH-Px,MDA,SOD,and LPO in heart tissue were detected by microplate Elisa.The expression of SLC7A11 and GPX4 proteins in the myocardium of mice was determined by immunohistochemistry and Western blot.2.Cell experiment: H9c2 rat cardiomyocytes were treated with doxorubicin concentration gradient to establish a model of doxorubicin cardiomyocyte injury;Myocardial cells were also treated with liquiritin.The experiment was divided into 4 groups: normal group(Control group),doxorubicin group(DOX group),doxorubicin +liquiritin low-dose group(DOX+LIQ L group),doxorubicin + liquiritin high-dose group(DOX+LIQ H group).After 24 h of processing,CCK8 was used to detect cell viability.Cell necrosis was detected by LDH,MDA content was measured by microplate Elisa,ROS level was detected by flow cytometry,and SLC7A11 and GPX4 protein levels were detected by Western Blot.Result:1.Animal experiments: 1)Compared with the control group,the body weight and cardiac weight coefficient of mice in the DOX group were significantly reduced,and the morphology and structure of myocardial cells were disturbed;Serum CK activity,CTn T and LDH contents increased significantly.The cardiotoxicity induced by doxorubicin can be alleviated by liquiritin intervention.2)Compared with the DOX group,the GSH/GSH-Px/SOD activities of control were significantly increased after treatment with liquiritin,and MDA and LPO contents were decreased;and significantly restored SLC7A11 and GPX4 protein levels.2.Cell experiments: 1)Compared with the Control group,adriamycin treatment resulted in H9c2 cell damage,such as decreased cell viability and significantly increased necrosis;SLC7A11 and GPX4 protein levels were significantly reduced.2)Compared with the DOX group,treatment with liquiritin increased cell viability and reduced cell necrosis;Moreover,MDA content and ROS level of lipid peroxidation were decreased.And increased SLC7A11 and GPX4 protein expression.Conclusion:1.Liquiritin has a protective effect on doxorubicin-induced cardiotoxicity.2.Liquiritin may exert anti-doxorubicin-induced cardiotoxicity by inhibiting ferroptosis of cardiomyocytes.3.Liquiritin regulates SLC7A11/GPX4 signal path to prevent doxorubicin-induced cardiotoxicity.