Carvacrol alleviates diabetic cardiomyopathy in rats: Targeting Cuproptosis pathway.

Diabetic cardiomyopathy (DCM) is a myocardial injury induced by chronic hyperglycemia. Recent literature has reported that hyperglycemia causes cardiac copper overload, triggering copper-induced cell death (cuproptosis). Copper leads to the dysregulation of ferredoxin-1 (FDX-1) and lipoic acid synthase (LIAS), two enzymes essential for the lipoylation process in the Krebs cycle, and are considered key markers of cuproptosis. We aim to explore the protective effects of carvacrol (CAR) against DCM by targeting cuproptosis. Diabetes was induced by a high-fat diet/streptozotocin (35 mg/kg) model. Rats were divided into: normal control, CAR control, diabetic group, and diabetic rats treated with CAR (20 mg/kg) or valsartan (30 mg/kg) for six weeks. The following were assayed: blood glucose, insulin, copper, serum cardiac biomarkers (creatine kinase-MB, cardiac troponin-I, aspartate aminotransferase, and lactate dehydrogenase), lipid peroxides, reduced glutathione (GSH), superoxide dismutase (SOD), inflammatory markers, copper transporter-1 (CTR1, copper importer), ATP7A and ATP7B (copper exporters), heat shock protein-70 (HSP-70), FDX-1 and LIAS. Pathological changes and fibrosis were detected. The diabetic group showed significant increases in serum cardiac biomarkers, cardiac levels of inflammatory cytokines and lipid peroxides, while GSH and SOD decreased. This was accompanied by increased copper, HSP-70, CTR1, and FDX-1, along with reduced ATP7A, ATP7B, and LIAS in cardiac tissues, indicating copper overload and cuproptosis. Histological examination revealed myocardial cell necrosis, nuclear enlargement, and collagen accumulation. Treatment with CAR ameliorated all deviations mentioned above. These findings highlight the cardioprotective effects of CAR against DCM through the normalization of cardiac copper homeostasis and inhibition of cuproptosis.