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bioRxiv · 10.1101/2025.06.24.661365

Integrated Omics Approach to Delineate the Mechanisms of Doxorubicin-Induced Cardiotoxicity

Dabour, M. S.·Abdelgawad, I. Y.·Sadaf, B.·Daniel, M. R.·Grant, M. K. O.·Blaes, A. H.·Jacobson, P. A.·Zordoky, B. N.
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Abstract

Doxorubicin (DOX) is an effective chemotherapy whose clinical utility is limited by cardiotoxicity. To investigate underlying mechanisms, we employed a multi-omics approach integrating transcriptomic and proteomic profiling leveraging established mouse models of chronic DOX- induced cardiotoxicity. 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, a temporal comparison was conducted between DEPs in the mice hearts 4 days and 6 weeks post-DOX. 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 hours post-DOX. Gene set enrichment analysis (GSEA) revealed upregulated pathways including p53 signaling, apoptosis, and unfolded protein response. Integrated omics analysis revealed 2,089 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. This integrated-omics study reveals key molecular pathways and temporal changes in DOX-induced cardiotoxicity, identifying potential biomarkers for future cardioprotective strategies.

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Dabour, M. S., Abdelgawad, I. Y., Sadaf, B., Daniel, M. R., Grant, M. K. O., Blaes, A. H., Jacobson, P. A., Zordoky, B. N.. 2025-06-27. Integrated Omics Approach to Delineate the Mechanisms of Doxorubicin-Induced Cardiotoxicity. https://doi.org/10.1101/2025.06.24.661365

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