Abstract <p>Doxorubicin (DOX) is a potent chemotherapeutic agent widelyused to treat various malignant neoplasms. However, its clinicaluse is limited by dose-dependent cardiotoxicity, leading to significant cardiovascularcomplications such as chronic heart failure, arrhythmias, and myocardialinfarction. The pathogenesis of DOX-induced myocardial injury involvesa complex interplay of biochemical and molecular mechanisms. Mostpreclinical studies investigating DOX cardiotoxicity and cardioprotective strategieshave used tumor-free animal models, which offer a controlled environmentbut may not fully replicate clinical conditions where tumors exertindirect effects on the myocardium. Tumors are known to releasecytokines and undergo metabolic reprogramming, contributing to inflammatoryresponses, oxidative stress, and myocardial remodeling. These processescan alter cardiomyocyte sensitivity to DOX and affect its protectiveinterventions. This discrepancy between experimental models andclinical reality raises important questions about the relevanceof tumor-free models for studying DOX-induced cardiotoxicity. Thisreview summarizes the current understanding of tumor-mediated effectson the myocardium and discusses the importance of selecting appropriateexperimental models that reflect both the presence and absence oftumor pathology for evaluating cardioprotective interventions. Addressing thischallenge is essential to improving the predictive value of preclinicalresearch and advancing therapeutic strategies for DOX cardiotoxicity.</p>