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  3. Carvacrol alleviates diabetic cardiomyopathy in rats: Targeting Cuproptosis pathway

Carvacrol alleviates diabetic cardiomyopathy in rats: Targeting Cuproptosis pathway

  • Toxicol Appl Pharmacol. 2026 Jan:506:117636. doi: 10.1016/j.taap.2025.117636.
Hala Attia 1,  Aliah Alshanwani 2,  Nadin Alatrouzi 3,  Sara Ibrahim 3,  Alaa Alanteet 4,  Norah K Algarzae 2,  Asma Alonazi 4,  Maha Arafah 5,  Iman Hasan 4,  Rehab Ali 4,  Wedad Sarawi 4
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. Electronic address: [email protected].
  • 2 Department of Physiology, College of Medicine, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • 3 Pharm D program(,) College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • 4 Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
  • 5 Pathology Department, College of Medicine, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
PMID: 41232726 DOI: 10.1016/j.taap.2025.117636
Abstract

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.

Keywords

Carvacrol; Copper transporter-1; Cuproptosis; Diabetic cardiomyopathy; Ferrodoxin-1; Lipoic acid synthase.

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