Xiaojianzhong decoction inhibits gastric cancer progression and enhances 5-Fu efficacy by regulating the MAPK and PI3K-AKT signaling pathway.

[AIM OF THE STUDY] This study aims to investigate the pharmacological mechanisms underlying the enhancement of fluorouracil (5-Fu) efficacy by Xiaojianzhong decoction (XJZD) in the treatment of gastric cancer (GC).

[MATERIALS AND METHODS] Network pharmacology was utilized to assess the therapeutic pathways of XJZD in the treatment of GC. The results from the network pharmacology analysis were validated through MTT assays, flow cytometry, qPCR, and ELISA experiments. Additionally, metabolomics was applied to identify differential metabolites and clarify the primary metabolic pathways involved.

[RESULTS] XJZD inhibited the proliferation of GC-803 cells and induced apoptosis. Furthermore, the combination of XJZD with 5-Fu significantly upregulated the mRNA levels of JNK1, JNK2, while downregulating the mRNA levels of ERK1, ERK2 and p38. Additionally, XJZD +5-Fu treatment reduced the expression of PI3K, AKT, and mTOR in GC-803 cells, suggesting that XJZD enhances the therapeutic effect of 5-Fu by inducing apoptosis and modulating the MAPK and PI3K-AKT signaling pathways. Metabolomics analysis identified 16 key metabolites that primarily influence amino acid and energy metabolism.

[CONCLUSIONS] In this study, the potential therapeutic pathway of XJZD in combination with 5-Fu for the treatment of GC was identified through network pharmacology, in vitro validation, and metabolomics. The therapeutic mechanism of XJZD in GC involves the synergistic effects of multiple active ingredients, targets, and signaling pathways, as well as the modulation of amino acid and energy metabolism. These findings provide new insights into the pharmacological mechanisms underlying the combination of XJZD and 5-Fu in the treatment of GC.