Xijiajing Formula Regulates Nrf2/GPX4 to Prevent 5-Fluorouracil-Induced Cardiotoxicity in Mice

WANG Wenhui; WEI Xiaohong; XU Qianqian; LIN Hongyuan; PENG Mengqi; ZHANG Xiaowei; SHANG Hongcai

Abstract：Objective To explore the effect and mechanism of Xijiajing formula on 5-fluorouracil-induced cardiotoxicity in mice.Methods C57BL/6J mice were randomly divided into five groups:Control group,5-fluorouracil group,low-dose Xijiajing formula group,medium-dose Xijiajing formula group,and high-dose Xijiajing formula group.Each group was administered the corresponding drugs via intraperitoneal injection or gavage at a volume of 10 mL/kg.The cardiotoxicity model was established by intraperitoneal injection of 5-fluorouracil at a dose of 5 mg/mL once a week for 4 weeks.In addition to the 5-fluorouracil injection,the Xijiajing formula groups were administered low,medium,or high doses of Xijiajing formula(0.552 5 g/mL,1.105 g/mL,2.210 g/mL)via gavage once daily for 4 weeks.After the 4-week intervention,echocardiography was performed to evaluate changes in cardiac function and structure.ELISA was used to measure myocardial injury markers and assess oxidative stress levels in mice.HE and Masson staining were employed to evaluate morphological changes and myocardial fibrosis in cardiac tissues.Western blotting was used to detect the expression of Nrf2/GPX4 proteins in myocardial tissues.Results Compared to the Control group,the 5-fluorouracil group showed a significant decrease in LVEF and LVFS(P<0.05),a significant increase in myocardial injury markers LDH and CK-MB levels(P<0.05),disordered myocardial fiber arrangement,and increased collagen fibers.In comparison to the 5-fluorouracil group,the Xijiiajing formula group exhibited improved LVEF and LVFS,reduced LDH and CK-MB levels,ameliorated myocardial pathological damage,and alleviated myocardial fibrosis.Further research found that 5-fluorouracil significantly increased the oxidative stress indicators MDA and ROS levels in mice(P<0.05),decreased the expression levels of antioxidant products GSH and SOD(P<0.05),and decreased the levels of antioxidant proteins Nrf2 and GPX4 in myocardial tissue(P<0.05).In contrast,the Xijiiajing formula group significantly inhibited the oxidative stress response induced by 5-fluorouracil.Conclusion Xijiajing formula may alleviate cardiotoxicity by activating the Nrf2/GPX4 antioxidant system,promoting the expression of antioxidant enzymes,and inhibiting the oxidative stress response induced by 5-fluorouracil.