NADPH Oxidases in Cancer Therapy-Induced Cardiotoxicity: Mechanisms and Therapeutic Approaches

Cancer therapy-induced cardiotoxicity remains a significant clinical challenge, limiting the efficacy of cancer treatments and impacting long-term survival and quality of life. NADPH oxidases, a family of enzymes that are able to generate reactive oxygen species (ROS), have emerged as key players in the pathogenesis of cardiotoxicity associated with various cancer therapies. This review comprehensively examines the role of NADPH oxidases in cancer therapy-induced cardiotoxicity, elucidating the underlying mechanisms and exploring potential therapeutic approaches. We discuss the structure and function of NADPH oxidases in the cardiovascular system and their involvement in cardiotoxicity induced by anthracyclines and ionizing radiation. The molecular mechanisms by which NADPH oxidase-derived ROS contribute to cardiac injury are explored, including direct oxidative damage, activation of pro-apoptotic pathways, mitochondrial dysfunction, vascular damage, inflammation, fibrosis, and others. Furthermore, we evaluate therapeutic strategies targeting NADPH oxidases, such as specific inhibitors, antioxidant therapies, natural products, and other cardioprotectors. The review also addresses current challenges in the field, including the need for isoform-specific targeting and the identification of reliable biomarkers. Finally, we highlight future research directions aimed at mitigating NADPH oxidase-mediated cardiotoxicity and alleviating cardiovascular side effects in cancer survivors. By synthesizing current knowledge and identifying knowledge gaps, this review provides a rationale for future studies and the development of novel cardioprotective strategies in cancer therapy.