Integration of transcriptomics, metabolomics, and lipidomics reveals the mechanisms of doxorubicin-induced inflammatory responses and myocardial dysfunction in mice

Doxorubicin (DOX) is an anthracycline antineoplastic agent that has limited clinical utility due to its dose-dependent cardiotoxicity. Although the exact mechanism remains unknown, inflammatory responses have been implicated in DOX-induced cardiotoxicity (DIC). In this study, we analyzed the transcriptomic, metabolomic as well as lipidomic changes in the DOX-treated mice to explore the underlying mechanisms of DIC. We found that continuous intraperitoneal DOX injections (3 mg/kg/d) for a period of five days significantly induced cardiac dysfunction and cardiac injury in male C57BL/6 J mice (8 weeks old). This corresponded to a significant increase in the myocardial levels of IL-4, IL-6, IL-10, IL-17 and IL-12p70. Furthermore, inflammation-related genes such as Ptgs2, Il1b, Cxcl5, Cxcl1, Cxcl2, Mmp3, Ccl2, CCL12, Nfkbia, Fos, Mapk11 and Tnf were differentially expressed in the DOX-treated group, and enriched in the IL-17 and TNF signaling pathways. Besides, Amino acids, Peptides, imidazoles, toluenes, hybrid Peptides, fatty acids and lipids such as Hex1Cer, Cer, SM, PG and ACCa were significantly associated with the expression pattern of inflammation-related genes. In conclusion, the integration of transcriptomic, metabolomic and lipidomic data identified potential new targets and biomarkers of DIC.

Cardiotoxicity; Doxorubicin; Inflammation; Lipidomics; Metabolome; Transcriptome.