Ellagic Acid Ameliorates Diabetic Cardiomyopathy by Inhibiting Ferroptosis Through the Modulation of the SIRT1/p53 Pathway in Streptozotocin-Induced Diabetic Rats

Abstract

Background: Diabetic cardiomyopathy (DCM) involves ferroptosis, an iron-dependent cell death pathway. Ellagic acid (EA), a natural antioxidant flavonoid, may offer therapeutic potential; however, its mechanisms in DCM remain unexplored. Objectives: This study investigated the cardioprotective effects of EA in experimental DCM, focusing on its capacity to mitigate ferroptosis via the sirtuin 1 (SIRT1)/p53 pathway. Methods: The EA (25, 50, or 100 mg/kg/day) was orally administered to streptozotocin (STZ)-induced diabetic rats for 60 days. We assessed cardiac function, histology, metabolic parameters, oxidative stress, inflammation, and key markers of ferroptosis and the SIRT1/p53 axis. Data were analyzed by one-way analysis of variance (ANOVA) with Tukey's post-hoc test. Results: The EA treatment dose-dependently attenuated cardiac hypertrophy, myocardial injury, and metabolic dysregulation, with maximal benefits at 100 mg/kg. It also reduced oxidative stress and inflammation. Crucially, EA inhibited ferroptosis, as evidenced by reduced iron overload and upregulation of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). These benefits were associated with the upregulation of SIRT1 and downregulation of p53 in cardiac tissue. Conclusions: The EA mitigates DCM by suppressing ferroptosis, potentially through modulation of the SIRT1/p53 pathway, thereby improving cardiac function and metabolic homeostasis. However, as this study utilized an STZ-induced model of type 1 diabetes, further research is warranted to confirm its efficacy in type 2 diabetic contexts.