Doxorubicin treatment induced dynamic remodeling of cardiac signaling, upregulating p53 signaling and apoptosis pathways, and significantly elevating plasma SERPINA3 in breast cancer patients.
This integrated omics study delineates the molecular mechanisms of doxorubicin-induced cardiotoxicity, identifying SERPINA3 as a potential biomarker.
Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent whose clinical utility is limited by cardiotoxicity. To investigate underlying mechanisms, we employed a multi-omics approach integrating transcriptomics and proteomics, leveraging established mouse models of chronic DOX-induced cardiotoxicity. Methods: Five-week-old male mice received weekly DOX (4 mg/kg) or saline injections for six weeks, with heart tissues harvested 4 days post-treatment. Differentially expressed genes (DEGs) and proteins (DEPs) were identified by bulk RNA-seq and proteomics, validated via qPCR and Western blot, respectively. Key DEPs were validated in plasma samples from DOX-treated breast cancer patients. Additionally, temporal comparison was conducted between DEPs in the mice hearts 4 days and 6 weeks post-DOX. Results: RNA-seq revealed upregulation of stress-responsive genes (Phlda3, Trp53inp1) and circadian regulators (Nr1d1), with downregulation of Apelin and Cd74. Proteomics identified upregulation of serpina3n, thrombospondin-1, and epoxide hydrolase 1. Plasma SERPINA3 concentrations were significantly elevated in breast cancer patients 24 h post-DOX. Gene set enrichment analysis (GSEA) revealed upregulated pathways, including p53 signaling, apoptosis, and unfolded protein response. Integrated omics analysis revealed 2089 gene–protein pairs. GSEA of concordant gene–protein pairs implicated p53 signaling, apoptosis, and epithelial–mesenchymal transition in upregulated pathways, while oxidative phosphorylation and metabolic pathways were downregulated. Temporal comparison with a delayed timepoint (6 weeks post-DOX) uncovered dynamic remodeling of cardiac signaling, with early response dominated by inflammatory and apoptotic responses, and delayed response marked by cell cycle and DNA repair pathway activation. Conclusions: This integrated omics study reveals key molecular pathways and temporal changes in DOX-induced cardiotoxicity, identifying potential biomarkers for future cardioprotective strategies.
Dabour et al. (Thu,) conducted a other in Doxorubicin-induced cardiotoxicity. Doxorubicin vs. saline was evaluated on Differentially expressed genes and proteins. Doxorubicin treatment induced dynamic remodeling of cardiac signaling, upregulating p53 signaling and apoptosis pathways, and significantly elevating plasma SERPINA3 in breast cancer patients.