Exploring the cardioprotective potential of Hyphaene Thebaica L. extract, Bacillus-derived proteases, and vitamin E against doxorubicin-induced cardiotoxicity: Insights into mechanisms and Wnt/β-catenin/GSK3β signaling modulation

DOXorubicin (DOX) is an effective chemotherapy drug, but its use is restricted by severe cardiotoxicity. This study investigated the acute cardiotoxic effects of DOX, which still has limited investigation, focusing on its impact on histological and cardiac biomarkers, alongside the Wnt/β-catenin pathway. Furthermore, exploring the cardioprotective potential of fruit Hyphaene Thebaica L. (Doum) extract, Bacillus-derived proteases (Bp), and vitamin E against this toxicity. Optimizing doum extraction increased its phenolic yield. Phytochemical profiling with protocatechuic acid identified as the principal active compound and molecular docking analyses were then conducted to explore how doum extract (protocatechuic), Bacillus protease, and vitamin E interact with components of the Wnt/β-catenin signaling pathway. Forty rats were divided into five groups: control, DOX, and DOX co-treated with doum extract, Bacillus protease, or vitamin E. DOX disrupted the Wnt/β-catenin signaling pathway by increasing Wnt1 and Wnt3a expression while decreasing glycogen synthase kinase 3 beta (GSK3β) and Axin levels. This imbalance promoted β-catenin accumulation, leading to cardiotoxicity characterized by histological alterations and elevated cardiac biomarkers, including aspartate aminotransferase (AST), lactate dehydrogenase (LDH), cardiac troponin I (C-TnI), creatine kinase-MB (CK-MB), and B-type natriuretic peptide (BNP). All treatments showed marked cardioprotection supported by histology and cardiac biomarkers. BP notably reduced LDH and AST, while vitamin E decreased BNP, CK-MB, and C-TnI, indicating improved myocardial stability. All interventions modulated GSK3β, Axin, and Wnt1, with BP exerting the strongest effect on Wnt3a and β-catenin. Doum's benefits are mainly linked to its phenolic content, particularly protocatechuic acid. These findings highlight Wnt/β-catenin signaling as a key target in DIC and support the potential of natural agents such as Doum, BP, and vitamin E in mitigating cardiac injury.