Introduction: Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide. Morin, a natural flavonoid present in edible plants like mulberries, figs, and almonds, has gained attention for its health-promoting properties, including anti-inflammatory and anticancer effects. This study aimed to evaluate the anticancer efficacy and molecular mechanisms of morin in gastric cancer, focusing on the AGS cell line.

Methods: We adopted an integrated approach combining network pharmacology, molecular docking, molecular dynamics simulations (100 ns), and in vitro assays including MTT, apoptosis, ROS, mitochondrial membrane potential, cell cycle, and Western blotting to elucidate morin’s action against AGS cells.

Results: Network pharmacology analysis revealed 10 key targets including PIK3CD, JAK2, IGF1R, and ERBB4, primarily enriched in the PI3K/Akt signaling pathway. Molecular docking confirmed strong binding affinities of morin to PIK3CD (–11.01 kcal/mol), JAK2 (–10.53 kcal/mol), and IGF1R (–9.99 kcal/mol), with stable interactions validated by dynamics simulation. Morin induced dose- and time-dependent cytotoxicity in AGS cells with a 24 h IC₅₀ of ~10.7 µM and 48 h IC₅₀ of ~5.4 µM. Flow cytometry and staining assays revealed S and G₂/M phase arrest, chromatin condensation, and increased apoptotic cell populations. Morin disrupted mitochondrial membrane potential and enhanced ROS generation. Western blotting showed Bax upregulation, Bcl-2 downregulation, cytochrome c release, caspase-3 activation, and PARP cleavage. Notably, morin inhibited Akt phosphorylation (Ser473) and downstream mTORC1 targets (4E-BP1, S6K), suggesting dual mTORC1/2 pathway inhibition.

Conclusion: Morin exhibits strong anticancer potential against AGS gastric cancer cells by targeting the PI3K/Akt/mTOR axis and inducing apoptosis via mitochondrial dysfunction. Its dietary origin further supports its promise as a functional food-based therapeutic candidate for GC.