(-)-Guaiol Inhibits Lung Cancer via PPARG-Dependent Fatty Acid Oxidation

Zhen-Yu Zhao, Bo Zhang, Ying-Bin Luo, Xing-Yu Wang, Yu-Li Wang, Xi Wang, Jian-Hui Tian,  Jian-Chun Wu,  Yan Li

Abstract:

The objective of this study was to explore the effect of (-)-guaiol on lung cancer using experimental validation, mRNA sequencing, and network pharmacology. Potential targets of (-)-guaiol and lung cancer were identified through SwissTargetPrediction, TCMSP, PharmMapper, OMIM, GeneCards, and DisGeNET databases. Common targets were analyzed using PPI network, topological screening, and functional enrichment using STRING, Cytoscape, and Metascape. Molecular docking with core targets was performed, along with molecular dynamics. In vitro assays (cell counting kit-8 assay, colony formation, wound healing, Transwell, western blot) and in vivo studies (subcutaneous xenograft modeling in nude mice, immunohistochemistry, mRNA sequencing) were conducted to validate the anti-tumor effects and mechanisms of (-)-guaiol compared with the control group. Through multi-database prediction, 153 (-)-guaiol targets and 91 common lung cancer targets were identified. Protein-protein interaction (PPI) network analysis screened 21 core targets (including ESR1, EGFR, etc.). GO and KEGG enrichment analyses revealed that these targets are involved in the regulation of pathways such as fatty acid metabolism. Molecular docking and molecular dynamics results demonstrated that (-)-guaiol possessed a favorable binding affinity toward the target proteins SRC, PTGS2, GSK3B, PPARG, ESR1, and HSP90AA1. mRNA sequencing indicated that the gene expression levels of both PPARG and CD36 were downregulated in lung cancer tissues of mice treated with (-)-guaiol compared with the control group. Combining the results of molecular docking, molecular dynamics, and mRNA sequencing, we selected the PPARG-related signaling pathway for subsequent experiments. Both in vivo and in vitro experiments validated that (-)-guaiol inhibits lung cancer cell proliferation, invasion, and xenograft tumor growth in mice by downregulating the PPARG pathway. To conclude, our results demonstrated that (-)-guaiol suppresses lung cancer progression through downregulation of the fatty acid oxidation-related pathway mediated by PPARG.