Cardio-Oncology: Molecular Mechanisms of Chemotherapy-Induced Cardiotoxicity and Cardioprotection

Background: The expanding field of cardio-oncology has brought increasing attention to the cardiovascular complications of cancer therapies, particularly chemotherapy-induced cardiotoxicity (CIC). Agents such as anthracyclines, trastuzumab, and tyrosine kinase inhibitors have significantly improved cancer survival but are associated with acute and chronic cardiac dysfunction. Understanding the molecular mechanisms underlying CIC is critical to developing effective cardioprotective strategies without compromising oncologic efficacy. Recent advances have revealed that cardiotoxicity arises from a complex interplay of oxidative stress, mitochondrial injury, DNA damage, impaired autophagy, and dysregulated signaling pathways in cardiomyocytes. Methods and Results: This review synthesizes preclinical and clinical data elucidating the molecular basis of CIC and highlights key mechanisms including topoisomerase IIβ–mediated DNA damage, reactive oxygen species (ROS) generation, and disruption of neuregulin-1/ErbB signaling. Mitochondrial dysfunction plays a central role, with loss of membrane potential, altered calcium homeostasis, and impaired mitophagy contributing to cardiomyocyte death. Inflammatory activation and endothelial injury further exacerbate cardiac damage and promote fibrotic remodeling. Emerging cardioprotective approaches include dexrazoxane, mitochondrial-targeted antioxidants, beta-blockers, ACE inhibitors, and novel agents modulating PI3K-Akt, AMPK, and sirtuin pathways. Genetic susceptibility and circulating biomarkers such as high-sensitivity troponins, natriuretic peptides, and microRNAs are being investigated for early detection and personalized risk assessment. Conclusion: Chemotherapy-induced cardiotoxicity is driven by multifaceted molecular insults that compromise myocardial integrity and function.