FOXO3 mediated gene expression modulates doxorubicin sensitivity in human cardiomyocytes.

Anthracyclines such as doxorubicin (DOX) are widely used and effective chemotherapeutic agents, but their clinical use is limited by dose-dependent cardiotoxicity, known as anthracycline-induced cardiotoxicity (AIC). Previously, we identified FOXO3 as a key transcription factor involved in cardiomyocyte stress response pathways. However, its precise role in modulating DOX sensitivity remains incompletely understood. This study aims to investigate the role of FOXO3 in cardiomyocyte transcriptional regulation and its impact on DOX-induced stress responses. By analyzing transcriptomic alterations in FOXO3-deficient cells, we seek to deepen the knowledge on FOXO3 and its potential role in cardioprotection. We generated a novel RNA sequencing dataset from immortalized human cardiomyocytes (hCMs) treated with DOX to compare global gene expression changes between FOXO3-depleted and control cells. Functional pathway analysis was conducted to identify dysregulated biological processes. FOXO3 nuclear translocation following DOX exposure was assessed through immunofluorescence, and key transcriptional changes were validated using RT-qPCR. We observed that DOX treatment induces FOXO3 nuclear translocation in hCMs and that FOXO3 depletion alters the transcriptional landscape of cardiomyocytes under basal conditions as well as after DOX exposure. Deregulated expression of genes related to DNA repair, oxidative stress response and apoptotic signaling, may explain the increased DOX sensitivity of FOXO3 depleted hCMs.