Integrative Metabolomics and Ionomics Identify Organ-Specific Responses Associated with Cisplatin Treatment in Mice.

Abstract

Background: Cisplatin is a widely used chemotherapeutic agent effective against various malignant tumors. However, its clinical application is limited by severe toxic side effects on multiple vital organs. Understanding the systemic metabolic and elemental alterations associated with cisplatin is essential for developing strategies to mitigate its toxicity.

Methods: An integrative metabolomics and ionomics approach was employed to investigate organ-specific responses to cisplatin treatment in mice. Gas chromatography-mass spectrometry (GC-MS) and inductively coupled plasma-mass spectrometry (ICP-MS) were used to analyze metabolic and elemental changes in multiple organs, including the heart, liver, spleen, lungs, kidneys, cortex, hippocampus, brown adipose tissue, and blood. Histopathological evaluation was also performed to complement biochemical analyses.

Results: Multivariate statistical analysis indicated that cisplatin was accompanied by significant changes in the levels of several key metabolites, including amino acids, fatty acids, and tricarboxylic acid cycle intermediates. A total of 9 metabolic pathways were implicated, particularly those involved in amino acid biosynthesis, energy metabolism, and redox regulation. In parallel, notable variations in metal ion concentrations, such as Ag, Na, Ca, Zn, Cu, Mg and Fe, were observed across organs. These changes may be linked to alterations in enzyme activity and antioxidant functions.

Conclusion: This study provides a comprehensive overview of metabolic and elemental disturbances in vital organs correlated with cisplatin exposure. The findings suggest that modulation of specific metabolites and trace elements may help reduce cisplatin toxicity. The integrative omics approach offers novel insights into the pathways potentially underlying chemotherapy-induced side effects and highlights possible therapeutic targets.