Cardioprotective strategies against doxorubicin-induced cardiotoxicity: A review from standard therapies to emerging mitochondrial transplantation

Abstract

Doxorubicin (DOX), a widely used chemotherapeutic agent, is effective against a broad spectrum of malignancies but is limited by its dose-dependent and potentially irreversible cardiotoxicity. DOX-induced cardiomyopathy can lead to progressive cardiac dysfunction and heart failure, significantly impacting patient survival and quality of life. The pathogenesis of this cardiotoxicity is multifactorial, involving excessive reactive oxygen species production, mitochondrial dysfunction, calcium dysregulation, ferroptosis, DNA damage, impaired autophagy, inflammation, and cardiomyocyte death. Current cardioprotective strategies-including β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and dexrazoxane-provide only partial protection and are insufficient to fully prevent long-term cardiac damage. In recent years, mitochondria-targeted therapies have gained attention due to the central role of mitochondrial injury in DOX cardiotoxicity. Therapeutic interventions aimed at modulating mitophagy, mitochondrial dynamics, oxidative stress, and inflammation have shown promise in preclinical studies. Among these, mitochondrial transplantation (MTx) represents an innovative and emerging strategy that directly restores mitochondrial function in injured cardiomyocytes. Preclinical studies demonstrate that MTx improves cardiac function, attenuates oxidative stress, reduces apoptosis, and enhances metabolic recovery in models of this cardiotoxicity. However, several critical challenges remain, including the long-term fate of transplanted mitochondria, immune compatibility, delivery methods, and safety. This narrative review provides a comprehensive overview of the molecular mechanisms underlying anthracycline-induced cardiac injury, evaluates current and emerging therapeutic approaches, and highlights the potential of MTx as a novel, mechanistically targeted therapy. Further research is needed to overcome translational barriers and evaluate clinical efficacy in human studies.

Keywords: Cardioprotection; Cardiotoxicity; Doxorubicin; Mitochondria targeted therapy; Mitochondria transplantation.