{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T06:52:39Z","timestamp":1781679159784,"version":"3.54.5"},"reference-count":114,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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\u00a0cell proliferation and induces apoptosis by regulating cell-cycle checkpoints and inhibiting oncogenic pathways, particularly Wnt\/\u03b2-catenin and the PI3K\/AKT\/mTOR axis. These coordinated effects facilitate apoptosis, autophagy modulation, and oxidative stress\u2013related cytotoxicity, and are further linked to reduced epithelial\u2013mesenchymal 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., GSK3\u03b2 and HNF4\u03b1) 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\u2013target relationships, elucidate BXD-mediated remodeling of the GC TEM to enhance therapeutic responsiveness.<\/jats:p>","DOI":"10.3389\/fphar.2026.1810848","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:05Z","timestamp":1781675765000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Banxia xiexin decoction and its bioactive metabolites: multi-targeted mechanisms for suppressing gastric cancer progression, reversing chemoresistance, and remodeling the tumor microenvironment"],"prefix":"10.3389","volume":"17","author":[{"given":"Donghan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Endocrinology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"Department of Endocrinology, Guangdong Provincial Hospital of Chinese Medicine","place":["Guangzhou, China"]},{"name":"Faculty of Chinese Medicine, Macau University of Science and Technology","place":["Macao, Macao SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqing","family":"Lin","sequence":"additional","affiliation":[{"name":"Faculty of Chinese Medicine, Macau University of Science and Technology","place":["Macao, Macao SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Deng","sequence":"additional","affiliation":[{"name":"Jianyang People\u2019s Hospital","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaonan","family":"Lu","sequence":"additional","affiliation":[{"name":"Wuming Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Guo","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"Department of Rehabilitation Medicine, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyu","family":"Yan","sequence":"additional","affiliation":[{"name":"Faculty of Chinese Medicine, Macau University of Science and Technology","place":["Macao, Macao SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehao","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"Department of Endocrinology, Guangdong Provincial Hospital of Chinese Medicine","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1159\/000519337","article-title":"Pathological diversity of gastric cancer from the viewpoint of background condition","volume":"103","author":"Abe","year":"2022","journal-title":"Digestion"},{"key":"B2","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.semcancer.2019.02.001","article-title":"Mechanisms of PTEN loss in cancer: it's all about diversity","volume":"59","author":"\u00c1lvarez-Garcia","year":"2019","journal-title":"Semin. 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