Doxorubicin-Induced Cardiotoxicity in Breast Cancer: Mechanistic Pathways, Pharmacogenomic Modifiers, and Translational Strategies.

Doxorubicin, a prototypical anthracycline, remains an important component of breast cancer therapy, although its use has declined with the availability of effective non-anthracycline regimens and is increasingly restricted to selected high-risk settings. At the same time, anthracyclines continue to serve as first-line therapy for multiple malignancies, including lymphomas, leukemias, and sarcomas, sustaining the broad clinical relevance of anthracycline-associated cardiotoxicity. This timely review synthesizes mechanistic, pharmacogenomic, and translational evidence on doxorubicin-induced cardiovascular toxicity. We highlight the interplay of DNA intercalation, topoisomerase II poisoning, redox cycling, mitochondrial dysfunction, and lipid metabolism as drivers of both anticancer efficacy and myocardial injury. Pharmacogenomic variants such as RARG, SLC28A3, and SLC22A3 (OCT3) modify individual susceptibility, offering investigational, genotype-informed avenues for cardioprotection. Emerging biomarkers-including troponins, sphingolipids, cell-free DNA, and immune signatures-show promise for early detection of cardiac injury. In parallel, tumor-intrinsic and microenvironmental mechanisms contribute to doxorubicin resistance, underscoring the need for integrated strategies that address efficacy and toxicity concurrently. Translational advances include established cardioprotective approaches such as dexrazoxane and liposomal formulations, alongside investigational strategies-including SGLT2 inhibitors, OCT3 blockade, and RARG agonists-that require prospective validation. Complementary efforts to overcome resistance encompass nanomedicine-based delivery, STAT3 inhibition, and RNA-directed therapeutics. By converging molecular mechanisms, pharmacogenomic insights, and biomarker discovery, this review outlines precision strategies to sustain doxorubicin benefit while minimizing cardiovascular harm.