Ferroptosis-like cell death induced by Amomi Fructus phenolic compounds in SGC7901 gastric cancer cells: a network pharmacology and experimental validation study.

BACKGROUND: To investigate the mechanism of Amomi Fructus phenolic compounds (AFPC) induced ferroptosis-like cell death in gastric cancer (GC) using a multiomics strategy combining network pharmacology, molecular dynamics simulations (MDS), and experimental validation.

METHODS: Potential targets of AFPC, ferroptosis, and GC were systematically analyzed via network pharmacology, protein-protein interaction (PPI) analysis, molecular docking, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, multi-omics databases (UALCAN, GEPIA, Kaplan-Meier Plotter, HPA, and TISCH1), MDS, and in vitro experiments on SGC7901 cells.

RESULTS: Two potential candidate bioactive compounds (gallic acid and quercetin) and five predicted central signaling nodes (TP53, HIF1A, IL-6, STAT3, and EGFR) were identified, among which only the IL-6/STAT3 pathway was experimentally validated. GO and KEGG analyses indicated that AFPC treatment in GC primarily involves oxidative stress, nuclear localization, p53 binding, and cancer-associated pathways. Molecular docking and simulations suggested that gallic acid and quercetin may act through modulating these predicted central signaling nodes. AFPC triggered ferroptosis by elevating Fe²+/malondialdehyde (MDA) and depleting glutathione (GSH), suppressing IL-6/STAT3 signaling, and inhibiting SGC7901 cell viability in a dose-dependent manner.

CONCLUSIONS: AFPC triggers ferroptosis-like cell death and inhibits GC progression associated with IL-6/STAT3 pathway inhibition, with gallic acid and quercetin as potential bioactive components, suggesting a plausible GC therapeutic strategy and the utility of multi-disciplinary approaches in herbal medicine mechanism research.