Investigating the role of serpinA3 in doxorubicin-induced cardiotoxicity

Drug-induced cardiotoxicity is a life-threatening side effect of anti-cancer treatment. Doxorubicin (DOX) is a widely used chemotherapeutic that induces cancer cell death through reactive oxygen species (ROS) production and topoisomerase IIα inhibition. Unfortunately, its usage has been demonstrated to worsen cardiac outcomes in cancer patients. Thus, there is a need for biomarkers to predict cardiotoxicity and create preventative interventions for DOX-induced cardiac injury. SerpinA3 is a target of clinical interest due to its overexpression in various cancers. However, it remains unknown if serpinA3 plays a role in cardiotoxicity. Here, we elucidated the role of serpinA3 in DOX-induced cardiotoxicity in both a human ventricular cardiomyocyte model and a murine primary cardiomyocytes model. DOX incubation resulted in an increase in serpinA3 expression in cardiomyocytes. It was linked to the excess production of mitochondrial ROS due to DOX treatment. Importantly, the increase in serpinA3 expression was correlated with a decrease in cardiotoxicity of cardiomyocytes. These findings highlight the critical role of serpinA3 in cardiomyocytes undergoing DOX-induced injury, and the potential of serpinA3 as a biomarker to predict cardiac injury development in patients receiving chemotherapy.