{"doi":"10.1101/2025.06.24.661365","title":"Integrated Omics Approach to Delineate the Mechanisms of Doxorubicin-Induced Cardiotoxicity","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":569249,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":337449,"name":"Ibrahim Y. Abdelgawad","orcid":"0000-0003-1399-4561","position":1,"is_corresponding":false},{"id":1030154,"name":"Bushra Sadaf","orcid":null,"position":2,"is_corresponding":false},{"id":1202009,"name":"Mary R. Daniel","orcid":null,"position":3,"is_corresponding":false},{"id":337448,"name":"Marianne Grant","orcid":"0000-0002-2963-4686","position":4,"is_corresponding":false},{"id":292152,"name":"Anne Blaes","orcid":"0000-0002-5433-4810","position":5,"is_corresponding":false},{"id":302262,"name":"Pamala A. Jacobson","orcid":"0000-0002-4145-7045","position":6,"is_corresponding":false},{"id":337451,"name":"Beshay N. Zordoky","orcid":"0000-0002-9358-4185","position":7,"is_corresponding":false},{"id":456139,"name":"Mohamed S. Dabour","orcid":"0000-0001-9261-4234","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:56:59.652443Z","pmid":"40667227","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}