Ferroptosis in Doxorubicin-Induced Cardiotoxicity: From Molecular Mechanisms to Therapeutic Strategies and Clinical Management Paradigms

Despite substantial advances in oncology and cardiovascular research, the clinical use of doxorubicin (DOX) remains constrained by significant cardiotoxicity; meanwhile, ferroptosis is now recognized as a central mechanism underlying DOX-induced cardiotoxicity (DIC). DOX disrupts myocardial iron homeostasis, impairs key antioxidant defense systems, and induces lipid metabolic reprogramming that promotes the accumulation of peroxidation-prone substrates, driving excessive lipid peroxidation and ferroptotic cell death. Ferroptosis also closely interacts with apoptosis, pyroptosis, and related pathways, forming a synergistic cell death network characterized by PANoptosis, which exacerbates cardiac injury. An integrated strategy encompassing primary prevention, targeted inhibition of core ferroptotic pathways, and systemic cardiac repair has emerged, which includes cardiac-targeted nanodelivery systems, selective inhibitors of key regulators such as glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthetase long-chain family member 4, as well as pharmacological activation of endogenous cardioprotective pathways. Clinical monitoring is also evolving from conventional cardiac functional indices toward early-warning approaches that incorporate ferroptosis-related circulating biomarkers, such as stress products, sensitive imaging metrics, including global longitudinal strain (GLS), and artificial intelligence-assisted analyses. Therefore, this review provides a systematic and comprehensive synthesis of recent advances in the molecular mechanisms, therapeutic interventions, and clinical management frameworks of ferroptosis in DIC, aiming to deepen understanding of the role of this process in the pathogenesis and treatment of DOX-induced cardiac injury.