Unraveling the Gut Microbiota-mediated Anti-tumor Mechanisms of ShenXia KuanZhong Decoction in Gastric Cancer: a Systems Biology and Dose-weighted Network Pharmacology Approach.

introductionGastric cancer (GC) remains a formidable global health issue with limited therapeutic options. ShenXia KuanZhong Decoction (SXKZD), a classical traditional Chinese medicine (TCM) formula, is used to manage GC; however, its anti-tumor mechanisms remain poorly understood. MATERIAL AND

methodsThe anti-GC effects of SXKZD were investigated in a GC model using dose-weighted network pharmacology, molecular docking, molecular dynamics (MD) simulations, and pharmacokinetic profiling. Its impacts on tumor metabolism, immunity, and gut microbiota were assessed. A gut microbiota-substrate-metabolite (GM-S-M) network was constructed, and key targets and pathways were analyzed using computational and experimental methods.

resultsSXKZD treatment significantly alleviated tumor progression in GC models. Network analysis revealed upregulated TNF and IL6 expression in GC, which SXKZD reduced, alongside enrichment in IL-17 and TNF signaling pathways. Molecular docking and MD simulations confirmed stable binding of Ginsenoside Rh2 and 3-Indolepropionic acid to TNF, with binding energies of -147.63 kJ/mol and - 98.63 kJ/mol, respectively. Pharmacokinetic profiling showed 3-Indolepropionic acid's high bioavailability, while GM-S-M analysis identified key microbial taxa (e.g., Lactobacillus plantarum, Akkermansia muciniphila) modulated by SXKZD, enhancing anti-tumor immunity and metabolism.To further confirm these computational predictions, in vitro CCK-8 assays revealed that GRh2 and IPA inhibited AGS cell growth in a concentration-dependent manner, with IC

conclusionsSXKZD mitigates GC by modulating gut microbiota and inhibiting TNF signaling, offering a mechanistic basis for its therapeutic potential in GC management.