Ito-Hagiwara Kanako, Hagiwara Jun, Endo Yusuke, Becker Lance B, Hayashida Kei
Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health System, Manhasset, NY, USA.
Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health System, Manhasset, NY, USA; Department of Emergency Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
Biomed Pharmacother. 2025 Aug;189:118315. doi: 10.1016/j.biopha.2025.118315. Epub 2025 Jul 3.
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.
阿霉素（DOX）是一种广泛使用的化疗药物，对多种恶性肿瘤有效，但受其剂量依赖性和潜在不可逆心脏毒性的限制。阿霉素诱导的心肌病可导致进行性心脏功能障碍和心力衰竭，显著影响患者的生存率和生活质量。这种心脏毒性的发病机制是多因素的，包括活性氧产生过多、线粒体功能障碍、钙调节异常、铁死亡、DNA损伤、自噬受损、炎症和心肌细胞死亡。目前的心脏保护策略，包括β受体阻滞剂、血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂、他汀类药物和右丙亚胺，仅提供部分保护，不足以完全预防长期心脏损伤。近年来，由于线粒体损伤在阿霉素心脏毒性中的核心作用，线粒体靶向治疗受到关注。旨在调节线粒体自噬、线粒体动力学、氧化应激和炎症的治疗干预在临床前研究中显示出前景。其中，线粒体移植（MTx）是一种创新的新兴策略，可直接恢复受损心肌细胞的线粒体功能。临床前研究表明，在这种心脏毒性模型中，MTx可改善心脏功能、减轻氧化应激、减少细胞凋亡并促进代谢恢复。然而，仍存在几个关键挑战，包括移植线粒体的长期命运、免疫相容性、递送方法和安全性。这篇叙述性综述全面概述了蒽环类药物诱导心脏损伤的分子机制，评估了当前和新兴的治疗方法，并强调了MTx作为一种新型、具有机制靶向性治疗方法的潜力。需要进一步研究以克服转化障碍并评估人体研究中的临床疗效。
