Objective To investigate the effect of puerarin(Pue)on ferroptosis in myocardial cells of rats with diabetic cardiomyopathy(DCM)and to analyze its potential mechanisms.Methods A DCM rat model was established by high-fat,high-sugar diet combined with streptozotocin injection.The successfully modeled rats were randomly divided into DCM group,low-dose Pue group(125 mg/kg,gavage),high-dose Pue group(250 mg/kg,gavage)and valsartan group(30 mg/kg,gavage),with 10 rats in each group.Another 10 healthy SD rats were selected as blank control group.At the end of treatment,fasting blood glucose,tail artery blood pressure(BP)total cholesterol(TC),triglycerides(TG)and low-density lipoprotein cholesterol(LDL-C)levels were measured in all groups.The cardiac function related indicators[left ventricular ejection fraction(LVEF),left ventricular fractional shorten-ing(LVFS),left ventricular end-systolic diameter(LVDs)and left ventricular end-diastolic diameter(LVDd)]of rats in each group were recorded by ultrasonic apparatus.Histopathological changes in myocardial tissues were observed using hematoxylin-eosin(HE)staining and TUNEL staining.Levels of glutathione peroxidase(GSH-Px),superoxide dismutase(SOD),reactive oxygen species(ROS),malondialdehyde(MDA)and Fe2+were detected using enzyme-linked immunosorbent as-say(ELISA)kits.Western blotting was used to detect the expression levels of glutathione peroxi-dase 4(GPX4),long-chain acyl-CoA synthetase 4(ACSL4)and proteins involved in the protein kinase B/glycogen synthase kinase-3β(AKT/GSK-3β)signaling pathway.Results Compared with the blank control group,the DCM group exhibited disordered or fractured myocardial fibers and significant inflammatory cell infiltration.The apoptosis rate,LVDs,LVDd,blood glucose,BP,TC,TG,LDL-C,ROS,MDA,Fe2+and ACSL4 protein expression levels in the DCM group were signifi-cantly higher,and LVEF,LVFS,GSH-Px as well as SOD and the protein expression levels of GPX4,phosphorylated(p)-AKT,p-GSK-3β and p-PI3K were lower than those in the blank group(P＜0.05).Compared with the DCM group,the low-dose Pue group,high-dose Pue group and valsartan group showed reduced fractured myocardial fiber or disarray,more regular arrangement of myocardial fibers,and decreased inflammatory cell infiltration.The apoptosis rate,LVDs,LVDd,blood glucose,BP,TC,TG,LDL-C,ROS,MDA,Fe2+and ACSL4 protein expression levels in the low-dose Pue group,high-dose Pue group and valsartan group were significantly lower,and LVEF,LVFS,GSH-Px as well as SOD and the protein expression levels of GPX4,p-Akt,p-GSK-3 βand p-PI3K were significantly higher than those in the DCM group(P＜0.05),and the effect was more significant in the high-dose Pue group.Conclusion Pue treatment can effectively improve the metabolic level of DCM rats,inhibit the pathological damage and apoptosis of cardiomyocytes,alle-viate oxidative stress,and thereby improving the cardiac function of DCM rats.Its mechanism of ac-tion may be related to the inhibition of cardiomyocyte ferroptosis mediated by the AKT/GSK-3βpathway.