Pharmacoproteomics reveals energy metabolism pathways as therapeutic targets of ivermectin in ovarian cancer toward 3P medical approaches.

OBJECTIVE: Ovarian cancer is the malignant tumor with the highest mortality rate in the female reproductive system, enormous socio-economic burden, and limited effective drug therapy. There is an urgent need to find novel effective drugs for ovarian cancer therapy. Our previous in vitro studies demonstrate that ivermectin effectively inhibits ovarian cancer cells and affects energy metabolism pathways. This study aims to clarify in vivo mechanisms and therapeutic targets of ivermectin in the treatment of ovarian cancer to establish predictive biomarkers, guide personalized treatments, and improve preventive strategies in the framework of 3P medicine. METHODS: A TOV-21G tumor-bearing mouse model was constructed based on histopathological data and biochemical parameters. TMT-based proteomic analysis was performed on tumor tissues from the different treatment groups. All significantly differentially abundant proteins were characterized by hierarchical clustering, Gene Ontology (GO) enrichment analyses, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. In addition, the data were integrated and analyzed with the proteomic data of clinical ovarian cancer tissues from our previous study and the proteomic data of ivermectin intervention in ovarian cancer cells to identify key regulators of ivermectin. RESULTS: Ivermectin (10 mg/kg) had a significant anti-ovarian cancer effect in mice, with a tumor inhibitory rate of 61.5%. Molecular changes in tumor tissue of ivermectin-treated mice were established, and protein-protein interaction (PPI) analysis showed that the main differential pathway networks included the TCA cycle, propanoate metabolism, 2-0xocarboxyacid metabolism, and other pathways. Integrating our previous clinical ovarian cancer tissue and cell experimental data, this study found that ivermectin significantly interfered with the energy metabolic pathways of ovarian cancer, including glycolysis, TCA cycle, oxidative phosphorylation, and other related pathways. CONCLUSIONS: This study evaluated the anti-ovarian cancer effect in vitro and in vivo, and its specific regulatory effect on energy metabolism. The expressions of drug target molecules in the energy metabolism pathway of ovarian cancer will be used to guide the diagnosis and prevention of ovarian cancer. The significant efficacy of ivermectin will be applied to the treatment of ovarian cancer and personalized medication. This has guiding significance for the clinical diagnosis, treatment, personalized medication, and prognosis evaluation of ovarian cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-024-00385-1.