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Introduction
Cardiovascular complications due to cancer therapy cause a significant reduction in treatment efficacy for patients with cancer (1). Doxorubicin (DOX) is a potent anthracycline that has been confirmed to cause long-term cardiovascular side effects and decrease the quality of life of cancer survivors, which eventually reduces the clinical application of DOX (2). Among the diverse mechanisms involved in the cardiotoxicity of DOX, the contribution of ferroptosis has been recently reported by an increasing number of studies (3–5).
Ferroptosis is a novel type of regulated cell death that is different from apoptosis and necrosis. It is an iron- and reactive oxygen species (ROS)-dependent cell death, characterized by the accumulation of ROS and inactivation of the cellular antioxidant glutathione (GSH), leading to redox dysregulation (6). Ferroptosis has been implicated in the pathological processes associated with carcinogenesis, degenerative diseases, stroke and kidney ischemia/reperfusion injury (7). Recently, ferroptosis was shown to exhibit a crucial role in DOX-induced cardiotoxicity. For instance, it has been documented that ferroptosis promoted DOX-induced cardiomyopathy and mortality in mice, whereas the ferroptosis inhibitor ferrostatin-1 and iron chelation ameliorate this process and effectively improve the survival rate of mice (4). In addition, mitochondrial ferroptosis has been shown to be a major cause of DOX-induced cardiotoxicity (2). It has also been reported that overexpression of GSH peroxidase 4 (GPX4) ameliorated cardiac impairment in mice, whereas GPX4 knockdown exacerbated this process (3). Therefore, inhibition of ferroptosis may effectively reduce DOX-induced cardiotoxicity.
Autotaxin (ATX) is a secreted enzyme encoded by the ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) gene, which is important for generating lysophosphatidic acid (LPA). The ATX/LPA pathway serves a major role in embryonic, vascular and neuronal development (8). Disturbances in normal ATX/LPA signaling are associated with the development of multiple diseases, including cardiovascular disease (9). A previous study reported that ENPP2/LPA protected cardiomyocytes from erastin-induced ferroptosis, indicating the inhibitory effect of ENPP2 on ferroptosis induction in cardiomyocytes (10). The transcription factor FoxO4, which is a member of the FoxO transcription factor family, is predicted to bind to the promoter of ENPP2. The FoxO proteins are involved in a variety of biological processes, including cell proliferation, oxidative stress response, metabolism, immunity and apoptosis (11). It has been suggested that FoxO4 may be involved in aggravating cardiovascular diseases (12). FoxO4...