The Chinese University of Hong Kong (CUHK) The Chinese University of Hong Kong, Hong Kong
Abstract: Anthracyclines, particularly doxorubicin (DOX), remain cornerstone chemotherapeutic agents for treating various malignancies, but their clinical application is severely limited by dose-dependent cardiotoxicity that can lead to irreversible heart failure. Current cardiac monitoring strategies primarily rely on cardiac troponin T, which only reflects acute cardiomyocyte death but cannot reveal ongoing cardiac degeneration or guide therapeutic interventions. microRNAs are stable in the bloodstream and can negatively regulate mRNA levels, thus they have emerged as biomarkers and therapeutic targets of diseases. We utilized a patient-derived human induced pluripotent stem cell-derived cardiomyocyte model to examine the secretion of microRNAs after DOX treatment. Unlike previous studies which focused on acute toxicity and cell death, we established a chronic DOX treatment model that demonstrated significant DNA damage and dysfunction to mimic cardiac degeneration in patients at later stages of this disorder. MicroRNAs were isolated from culture supernatants and subjected to RNA sequencing. Our analysis identified distinct microRNA signatures associated with DOX-induced cardiac injury. Parallel transcriptomic profiling revealed dysregulation of key pathways involved in DNA damage response, mitochondrial function, and cardiac stress. We next integrated our microRNA and mRNA data to reveal potential regulatory mechanisms underlying DOX-induced cardiotoxicity. This study not only provides novel circulating biomarkers for monitoring anthracycline-induced cardiac damage but also offers potential therapeutic targets for intervention, representing a significant advancement toward personalized cardio-oncology care and improved patient outcomes.
