Banxia xiexin decoction and its bioactive metabolites: multi-targeted mechanisms for suppressing gastric cancer progression, reversing chemoresistance, and remodeling the tumor microenvironment.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, primarily due to late diagnosis and limited benefit from surgery alone. Although chemotherapy, targeted agents, and immunotherapy have improved outcomes for selected patients, their clinical benefits are often limited by significant toxicity, acquired resistance, and the pronounced molecular heterogeneity of GC. Multi-target therapeutic approaches are therefore urgently needed. Banxia Xiexin Decoction (BXD), a classic Traditional Chinese Medicine formula widely used for gastrointestinal disorders, has emerged as a promising adjuvant candidate for GC treatment. However, the bioactive metabolites and molecular mechanisms of BXD have not been fully clarified. This review comprehensively summarizes current evidence on the anti-GC actions of BXD and its key bioactive metabolites. Mechanistically, BXD inhibits GC cell proliferation and induces apoptosis by regulating cell-cycle checkpoints and inhibiting oncogenic pathways, particularly Wnt/β-catenin and the PI3K/AKT/mTOR axis. These coordinated effects facilitate apoptosis, autophagy modulation, and oxidative stress-related cytotoxicity, and are further linked to reduced epithelial-mesenchymal transition (EMT), invasion, migration, and angiogenesis. The major bioactive metabolites of BXD, such as berberine, baicalin, wogonoside, and glycyrrhizin further reverse chemoresistance by downregulating drug-efflux and survival signaling, thereby enhancing sensitivity to standard agents such as cisplatin, 5-fluorouracil, oxaliplatin, and paclitaxel. BXD also shows potential in suppressing peritoneal metastasis by disrupting pre-metastatic niche formation and in improving anti-tumor immunity through downregulation of PD-L1 via the IL-6/JAK/STAT3 pathway, reduction of immunosuppression, and promotion of immunogenic cell death (ICD). Furthermore, BXD-associated regulation of metabolic reprogramming (e.g., GSK3β and HNF4α) may undermine GC cellular adaptability under therapeutic stress. These findings highlight BXD as a promising multi-component, multi-pathway adjuvant candidate for GC, exerting cooordinated effects on tumor cell survival, metastasis, drug resistance, metabolism, and immune regulation. Nevertheless, limitations of current studies include insufficient investigation of tumor microenvironmental (TME) components (particularly macrophages, exosomes, and mesenchymal stem cells) and a lack of standardized pharmacokinetic/pharmacodynamic characterization (PK/PD). Future research should integrate multi-omics, spatial transcriptomics, and rigorous preclinical and clinical trials to improve reproducibility, clarify active metabolite-target relationships, elucidate BXD-mediated remodeling of the GC TEM to enhance therapeutic responsiveness.