Mechanistic investigation of Chai Gui Zexie Decoction in treating non-small cell lung cancer: an integrated metabolomics and network pharmacology approach.
TL;DR
Chai Gui Zexie Decoction exerts therapeutic effects against NSCLC through a multi-component, multi-target mechanism involving the regulation of RTK signaling pathways and phenylalanine metabolism.
Abstract
This study aimed to elucidate the therapeutic mechanisms of Chai Gui Zexie Decoction against non-small cell lung cancer (NSCLC) through an integrated approach combining metabolomics, network pharmacology, and experimental validation. A subcutaneous NSCLC metastasis model was established in C57BL/6 mice using Lewis lung cancer cells. Mice were randomly assigned to model, low-dose, and high-dose Chai Gui Zexie Decoction groups (n = 6 per group). Tumor growth was monitored over 18 days. Serum metabolomics analysis using liquid chromatography-tandem mass spectrometry was performed to identify differential metabolites and blood-absorbed components. Network pharmacology was employed to predict therapeutic targets, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Western blotting was conducted to validate the expression of core targets (IGF1R, PTK2, SRC) in tumor tissues. High-dose Chai Gui Zexie Decoction significantly inhibited tumor growth compared to the model group (P < 0.05). Metabolomics identified 13 blood-absorbed components, primarily enriched in phenylalanine metabolism. Network pharmacology revealed 195 overlapping targets between the decoction and NSCLC, with 10 core targets identified, including SRC, PTK2, and IGF1R. KEGG analysis implicated key pathways such as PI3K-Akt signaling, EGFR TKI resistance, and Ras/MAPK signaling. Western blot validation confirmed that high-dose treatment significantly downregulated IGF1R, PTK2, and SRC protein expression in tumor tissues (P < 0.05). Chai Gui Zexie Decoction exerts therapeutic effects against NSCLC through a multi-component, multi-target mechanism involving the regulation of RTK signaling pathways and phenylalanine metabolism. These findings provide a scientific basis for its clinical application and highlight potential therapeutic targets for NSCLC treatment.