From prognostic modeling to drug discovery: a metabolism-guided strategy for herbal small-molecule screening in gastric cancer

Introduction Metabolic reprogramming and immune evasion are tightly linked in gastric cancer (GC), yet metabolic signatures are rarely leveraged to guide treatment decisions or herbal small molecule drug discovery. Methods We profiled glycolysis, lipid, and tyrosine metabolism pathways across the TCGA-STAD and GSE62254 cohorts, identified prognostic metabolic subtypes, and distilled these findings into a three-gene risk signature ( VCAN, NOS1, LCT ). The signature was validated in the external GSE62254 cohort and assessed for associations with immune cell infiltration patterns, tumor mutational burden, microsatellite instability status, and tumor immune dysfunction and exclusion (TIDE) scores. Rather than following the conventional compound-to-target screening paradigm, we reversed the pipeline: starting from the signature genes, we queried PubChem for herbal bioactive small molecules targeting the three signature proteins ( VCAN, NOS1, and LCT ) and evaluated candidates through molecular docking, 100-ns molecular dynamics simulations, and comprehensive ADMET profiling. The anti-GC activity of the leading candidate was further examined in AGS and HGC27 cells. Results Three prognostic metabolic subtypes with distinct survival outcomes and immune microenvironment compositions were identified. The model robustly stratified patients into high- and low-risk groups and showed significant correlations with immune cell infiltration patterns, tumor mutational burden, microsatellite instability status, and TIDE scores. Notopterol (a furanocoumarin) and amentoflavone (a biflavonoid) emerged as the most promising hits. Notopterol, in particular, exhibited favorable drug-like properties and potent anti-GC activity: it suppressed the proliferation and migration of AGS and HGC27 cells in a concentration-dependent manner. Discussion These findings establish a metabolism-driven prognostic framework and nominate notopterol as a lead herbal-derived small molecule for further development in gastric cancer therapy; its correlations with immunotherapy-related features indicate potential utility for immunotherapy patient selection.