α-Mangostin prevents diabetic cardiomyopathy by inhibiting oxidative damage and lipotoxicity through the AKT–FOXO1–CD36 pathway

Introduction Diabetic cardiomyopathy (DCM), a cardiac complication of diabetes, is the main cause of the high prevalence of heart failure and associated mortality in diabetic patients. Oxidative stress and lipid metabolism disorder-induced myocardial cell damage are part of the pathogenesis of DCM. In this study, we investigated the effects of alpha-mangostin (A-MG), a natural antioxidant extracted from mangosteen peel, on in vitro and in vivo DCM models. Methods H9C2 rat cardiomyocytes were treated with high glucose (HG) and palmitic acid (PA) for 24 h to establish an in vitro DCM cell model. Cell viability and cytotoxicity were evaluated after treatment with varying concentrations of A-MG (0.3, 1, 3, 9, or 27 μM) using Cell Counting Kit-8 (CCK8) and lactate dehydrogenase (LDH) assays. Flow cytometry assessment was used to detect apoptosis. Molecular mechanisms were investigated through transcriptome analysis, quantitative PCR (RT-qPCR), and Western blotting. Type 2 diabetic (T2D) mice, induced by feeding a high-fat diet (HFD) combined with low-dose streptozotocin (STZ), received either vehicle, low-dose A-MG (100 mg/kg/d), or high-dose A-MG (200 mg/kg/d) for 6 weeks. Cardiac function was assessed by echocardiography. H&E and Masson’s staining were used to evaluate cardiac tissue structure and fibrosis, and Western blotting was used to evaluate myocardial protein expression. Results In HG/F-induced H9C2 cells, A-MG (1 and 3 μM) significantly increased cell viability (p < 0.01) and reduced LDH release (p < 0.05). A-MG (3 μM) attenuated lipid accumulation (p < 0.05), normalized mitochondrial membrane potential (p < 0.01), and inhibited reactive oxygen species (ROS) generation (p < 0.05), malondialdehyde (MDA) production (p < 0.01), and apoptosis (p < 0.05). A-MG also inhibited the nuclear translocation of Forkhead box class O1 (FOXO1) (p < 0.05); reduced the expression of CD36 (p < 0.05), PPARα (p < 0.01), and CPT1β (p < 0.05) proteins; enhanced superoxide dismutase (SOD) activity (p < 0.05); and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) (p < 0.01), HO-1 (p < 0.05), and SOD2 (p < 0.05) protein expression levels. Further investigation in HG/F-induced H9C2 cells indicated that A-MG inhibits the uptake of fatty acids (FAs) by regulating the AKT/FOXO1/CD36 signaling pathway, reduces excessive β-oxidation of FAs mediated by PPARα/CPT1β through the inhibition of FOXO1 nuclear translocation, and stimulates the AKT/Nrf2/HO-1 signaling pathway to increase the cellular antioxidant capacity. In diabetic mice, low-dose A-MG treatment increased anti-oxidative stress capacity, decreased myocardial lipid accumulation, reduced fibrosis and cardiomyocyte apoptosis, and improved left ventricular contractile function. Conclusion Using both in vitro and in vivo DCM models, our study demonstrates that A-MG reduces lipid accumulation and excessive mitochondrial β-oxidation while enhancing antioxidant capacity. These results suggest that A-MG may be a novel therapeutic option for DCM.