Metabolomics profiling of doxorubicin-induced cardiotoxicity in mice with lung injury

Cardiotoxicity of cancer chemotherapeutics has received considerable attention in recent years.However, the effects of chemotherapy on cardiometabolic perturbation with lung injury have rarely been reported. Thus, we constructed a mouse model of myocardial injury superimposed on lung injury with a combination of bleomycin (BLM) and doxorubicin (DOX).C57BL/6J mice were randomly divided into four groups: control group (CON), BLM group (intratracheal infusion with single doses of 5 mg/kg), DOX group (intraperitoneal injection of 7.5 mg/kg/week, two weeks) and DOX+BLM group. The cardiac injury of mice was evaluated by serum biochemical parameters and histopathology.Cardiometabolic perturbation was investigated using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS).The results showed that, compared with the CON group, BLM alone caused lung injury yet with no significant effects on the cardiometabolic profile; DOX alone had significant perturbations in the cardiometabolic profile, and the main differential metabolites were amino acids, fatty acids, phospholipids, etc.; the combination of BLM and DOX caused more severe disturbance of cardiometabolic homeostasis in mice, especially accumulation of branched-chain amino acids.This study confirmed that DOX can lead to more significant changes in the cardiometabolic profile in the presence of lung injury, with an initial focus on the branched-chain amino acid metabolic pathway.This research provides scientific data for in-depth study of the cardiotoxicity mechanism of chemotherapeutic agents.