The Doxorubicin-Induced Myocardial Injury Model in Rodents: A Paradigm Shift?

Doxorubicin (DOX) is a potent chemotherapeutic agent widely used to treat various malignant neoplasms. However, its clinical use is limited by dose-dependent cardiotoxicity, leading to significant cardiovascular complications such as chronic heart failure, arrhythmias, and myocardial infarction. The pathogenesis of DOX-induced myocardial injury involves a complex interplay of biochemical and molecular mechanisms. Most preclinical studies investigating DOX cardiotoxicity and cardioprotective strategies have used tumor-free animal models, which offer a controlled environment but may not fully replicate clinical conditions where tumors exert indirect effects on the myocardium. Tumors are known to release cytokines and undergo metabolic reprogramming, contributing to inflammatory responses, oxidative stress, and myocardial remodeling. These processes can alter cardiomyocyte sensitivity to DOX and affect its protective interventions. This discrepancy between experimental models and clinical reality raises important questions about the relevance of tumor-free models for studying DOX-induced cardiotoxicity. This review summarizes the current understanding of tumor-mediated effects on the myocardium and discusses the importance of selecting appropriate experimental models that reflect both the presence and absence of tumor pathology for evaluating cardioprotective interventions. Addressing this challenge is essential to improving the predictive value of preclinical research and advancing therapeutic strategies for DOX cardiotoxicity.