Molecular insights into doxorubicin-induced cardiotoxicity and phytochemical-based cardioprotection: challenges and future strategies

Doxorubicin, an anthracycline antibiotic extensively used in cancer treatment, is limited by its dose-dependent cardiotoxicity caused by oxidative stress, mitochondrial dysfunction, inflammation, and cardiomyocyte apoptosis-ultimately leading to cardiomyopathy, heart failure, and decreased quality of life. Although dexrazoxane is the only FDA-approved cardioprotective agent, concerns about its long-term safety and potential interference with doxorubicin's antitumor effectiveness have increased the search for safer alternatives. This study investigates the cardioprotective effects of phytochemicals and herbal compounds that target key signaling pathways involved in doxorubicin-induced cardiotoxicity, specifically PI3K/Akt, AMPK/SIRT1, Nrf2/Keap1, NF-κB, and Akt/mTOR/GSK-3β. Despite promising preclinical evidence of their antioxidant, anti-inflammatory, and anti-apoptotic properties, the clinical use of phytochemicals is limited by issues such as low bioavailability, poor specificity, dose-dependent toxicity, variable pharmacokinetics, and lack of standardization. Therefore, innovative approaches-such as ligand-targeted delivery systems, nanotechnology-based formulations, and structural modifications of lead compounds-are essential to enhance their pharmacological properties, safety, and therapeutic effectiveness for effective cardioprotection against doxorubicin-induced toxicity.