From prognostic modeling to drug discovery: a metabolism-guided strategy for herbal small-molecule screening in gastric cancer
- 1Department of Traditional Chinese Medicine, The First Affiliated Hospital of Sun Yat-Sen University
- 2School of Chinese Medicine, Hong Kong Baptist University
Abstract
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.
Related
- Direct-to-Biology Strategy Accelerates CRBN-Targeting Molecular Glue Degrader Discovery
- Screening strategy versus drug efficacy: Revisiting the evidence for vaginal progesterone in short cervix
- Universal cervical length screening and vaginal progesterone: Distinguishing strategy effectiveness from treatment efficacy
- Assessing an educational strategy to improve community health provider-led provision of cervical cancer screening services in western Kenya: A secondary analysis of the Elimisha-HPV cluster-randomized controlled trial
- Identification and validation of prognostic characteristics of survival risk marker genes associated with ferroptosis and iron metabolism in breast cancer
BibTeX
@article{wu2026from,
title = {{From prognostic modeling to drug discovery: a metabolism-guided strategy for herbal small-molecule screening in gastric cancer}},
author = {Yingzi Wu and Jinhai Luo and Baoguo Sun and Zexiong Chen},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1907687},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1907687/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From prognostic modeling to drug discovery: a metabolism-guided strategy for herbal small-molecule screening in gastric cancer
AU - Yingzi Wu
AU - Jinhai Luo
AU - Baoguo Sun
AU - Zexiong Chen
PY - 2026
DA - 2026/11/03
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1907687
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1907687/full
AB - 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.
SN - 1663-9812
ER -