Cardiovascular Toxicity in Cancer Therapy: Potential Mechanisms of Ferroptosis and Treatment Strategies

Abstract

Highlights What are the main findings? Ferroptosis exerts a dual role in cardio-oncology. Targeted ferroptosis eliminates drug-resistant tumors, while activation in cardiovascular system induces anticancer therapy-related cardiovascular toxicity. Chemotherapy, targeted therapy, immunotherapy, and radiotherapy induce cardiac ferroptosis through disrupted iron homeostasis and impaired multiple antioxidant defense pathways. What are the implications of the main findings? This review establishes an integrated cardio-oncology framework linking tumor ferroptosis and cardiac ferroptosis, providing a mechanistic basis for balancing antitumor efficacy and cardiac safety. This review underscores an urgent need for the development of novel tissue-specific ferroptosis inhibitors and cardioprotective agents, as well as biomarker-based monitoring, to realize personalized management of anticancer therapy-related cardiovascular toxicity. Abstract Advances in anticancer therapies have substantially improved cancer survival but have also highlighted the growing challenge of cancer therapy-related cardiac dysfunction. Ferroptosis, an iron-dependent form of regulated cell death characterized by iron dysregulation, lipid peroxidation, and impaired antioxidant defense, has emerged as a promising strategy for eliminating therapy-resistant tumors. However, the lack of tissue specificity in ferroptosis regulation raises concerns regarding its potential contribution to cardiovascular injury during anticancer treatment. This review summarizes the dual roles of ferroptosis in cancer biology and cardio-oncology. We first discuss the molecular mechanisms governing ferroptosis, including iron metabolism, lipid peroxidation, and antioxidant defense systems. We then highlight the context-dependent roles of ferroptosis in tumor progression, immune regulation, and metabolic adaptation. Furthermore, we systematically review how chemotherapy, targeted therapy, immunotherapy, and radiotherapy contribute to ferroptosis-associated cardiovascular toxicity. Finally, we discuss emerging approaches to minimize cardiac injury, including tissue-specific ferroptosis-targeting and cardioprotective strategies. Understanding tissue-specific ferroptosis regulation may facilitate the development of safer and more precise therapeutic approaches in cardio-oncology.