Integrative Untargeted Metabolomics, Network Pharmacology, and Molecular Docking Identify Candidate Anti–Gastric Cancer Mechanisms of Zhishi Dahuang Decoction

ABSTRACT Zhishi Dahuang decoction (ZDD), a modified prescription derived from classical TCM formulae, remains poorly characterized regarding its material basis and molecular mechanisms against gastric cancer. In this study, ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) untargeted metabolomics was used to comprehensively profile the chemical constituents of ZDD, identifying 253 compounds; composite evidence‐based screening yielded 45 putative active components—including reported antitumor compounds and characteristic herbal constituents—primarily flavonoids, triterpenoid saponins, and anthraquinones. Integrating network pharmacology with gastric cancer transcriptomic data (GSE29272) identified 217 potential anti–gastric cancer targets, and protein–protein interaction (PPI) network analysis revealed hub targets including TP53, SRC, STAT3, EGFR, and AKT1, of which TP53, SRC, and STAT3 were selected as representative targets for molecular docking. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that these targets are mainly involved in classical tumor‐associated pathways, including PI3K‐Akt, MAPK, PD‐1/PD‐L1 immune checkpoint, and HIF‐1 signaling. Molecular docking showed that multiple core components exhibit favorable binding affinity with the three representative targets. These findings suggest that ZDD may exert anti–gastric cancer effects through synergistic multicomponent, multitarget, and multipathway regulation, providing a theoretical basis for further experimental verification of its mechanisms.