Vitex Simplicifolia Abates Cadmium-Induced Cardiotoxicity Through Antioxidant Activity and Keap1 Targeting

This study evaluated the cardioprotective potential of Vitex simplicifolia methanol extract (VSME) and explored its underlying mechanisms of action. Twenty-five male rats were assigned to five groups (n = 5). Group 1 served as the normal control, while groups 2-5 were exposed to 5 mg/kg body weight of cadmium chloride (CdCl₂) daily. Group 2 received no treatment, whereas groups 3 and 4 were treated with 200 and 400 mg/kg VSME, respectively, and group 5 received 10 mg/kg propranolol (standard drug), all for 21 days via oral administration. Biochemical and histopathological analyses of the heart were conducted post-treatment. Cadmium exposure significantly elevated cardiac malondialdehyde, triglycerides, cholesterol, low-density lipoprotein, creatine kinase, lactate dehydrogenase, and C-reactive protein, while reducing high-density lipoprotein, superoxide dismutase (SOD), catalase, and glutathione peroxidase. VSME treatment reversed these changes, restoring antioxidant status, lipid profile, cardiac biomarkers, and myocardial architecture. Molecular docking revealed strong binding affinities of VSME phytochemicals (kaempferol, isorhamnetin, luteolin) with Kelch-like ECH-associated protein 1 (Keap1), primarily through hydrogen bonds. These compounds exhibited superior drug-likeness, pharmacokinetics, and safety profiles compared to the standard Keap1 inhibitor, CPUY192018. These findings suggest that VSME may exert cardioprotective effects partly through antioxidant activity and potential interference with the Keap1-Nrf2 interaction, as supported by molecular docking.