Elucidating the toxic mechanism of doxorubicin-induced cardiac ferroptosis through network toxicology and molecular docking

Doxorubicin (DOX), a widely utilized chemotherapeutic agent, is restricted in clinical application due to its cardiotoxicity, with Ferroptosis being a pivotal factor in DOX-induced cardiotoxicity (DIC). DIC can be classified into chronic and acute types based on clinical manifestations. Both forms involve Ferroptosis, yet the underlying mechanisms are still unclear. This study aimed to investigate the molecular mechanisms of DIC Ferroptosis, including acute and chronic DIC, through network toxicology and molecular docking analysis, thereby proposing potential therapeutic targets. To achieve this, acute and chronic DIC models were established. A comprehensive assessment of cardiac function, myocardial injury, oxidative stress, and iron deposition was conducted. Transcriptome analysis uncovered distinct gene expression patterns and enrichment pathways related to Ferroptosis in the two models. Key genes (POMC in chronic DIC, and SNCA and S100A8 in acute DIC) were pinpointed via intersection analysis with genes associated with cardiomyopathy and Ferroptosis. Regulatory networks involving miRNAs and transcription factors were constructed. Potential therapeutic agents were predicted using molecular docking and subsequently validated. These findings deepened our understanding of the Ferroptosis mechanisms in DIC and offered novel personalized therapeutic strategies for preventing and treating DIC.

DOX-induced cardiotoxicity; Ferroptosis; Hormone metabolism; Personalized therapeutic strategies; ROS metabolism.