Molecular mechanisms, risk factors, and emerging cardioprotective strategies in doxorubicin-induced cardiotoxicity: a narrative review

Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent with proven efficacy against various solid and hematologic malignancies. However, its clinical application is significantly limited by cumulative and dose-dependent cardiotoxicity, which may ultimately lead to irreversible cardiomyopathy and heart failure. Understanding the underlying molecular mechanisms and identifying effective preventive strategies remain critical challenges in cardio-oncology. This narrative review summarizes the current evidence on the molecular and cellular mechanisms involved in doxorubicin-induced cardiotoxicity, based on a literature search of PubMed/MEDLINE, Scopus, and Web of Science from database inception until January 2025. Key pathogenic pathways include oxidative stress, mitochondrial dysfunction, topoisomerase IIβ-mediated DNA damage, calcium dysregulation, apoptosis, ferroptosis, inflammation, and fibrosis. Emerging evidence highlights the regulatory roles of non-coding RNAs (miRNAs, lncRNAs, and circRNAs) and major signaling pathways such as PI3K/Akt, MAPK, NF-κB, and the TLR4/NLRP3 inflammasome axis in modulating cardiac injury. In addition, biomarkers including troponin I, NT-proBNP, and advanced echocardiographic parameters such as global longitudinal strain (GLS) and global circumferential strain (GCS) are discussed for early detection. Current and emerging cardioprotective strategies, including dexrazoxane, antioxidant-based therapies, metabolic modulators, and nanoparticle-based drug delivery systems, are also reviewed and classified by their stage of clinical development, as most non-dexrazoxane strategies remain preclinical. Doxorubicin-induced cardiotoxicity is a multifactorial and complex process involving interconnected molecular pathways. Advances in mechanistic insights, early diagnostic biomarkers, and targeted cardioprotective interventions may improve patient outcomes and enable safer anticancer therapy. Future translational and clinical studies are required to validate novel preventive strategies and promote personalized approaches in cardio-oncology.