Network pharmacology, molecular docking, and In Vitro evaluation of morin against gastric cancer

Gastric cancer (GC) remains one of the most prevalent and lethal malignancies worldwide. Natural flavonoids are increasingly recognized for their therapeutic potential due to their multi-target actions and favourable safety profiles. Morin, a dietary flavonol found in several plants of the Rosaceae, Moraceae, and Fagaceae families, has not been well explored in GC. In this study, network pharmacology analysis identified ten major morin-associated hub genes (PIK3R3, PIK3CA, PIK3CB, PIK3CD, PIK3R2, PLCG1, JAK2, IGF1R, ZAP70, and ERBB4), several of which are key regulators of the PI3K-Akt signalling axis. Molecular docking showed strong binding affinities of morin toward PIK3CD (-11.01 kcal/mol), ZAP70 (-10.72 kcal/mol), JAK2 (-10.53 kcal/mol), IGF1R (-9.99 kcal/mol), PIK3CA (-9.79 kcal/mol), and ERBB4 (-8.83 kcal/mol). Molecular dynamics simulations of 500 ns, along with PCA, DCCM, FEL, and MM-GBSA analyses further confirmed stable interaction of morin with PIK3CA. In vitro, morin demonstrated selective cytotoxicity, with low IC₅₀ values in AGS (15.16 ± 0.02 μM) and NCI-N87 (15.85 ± 0.8 μM) GC cells, compared to a significantly higher IC₅₀ in normal MCF10A cells (101.97 ± 2.61 μM). Wound-healing assays showed that morin inhibits AGS cell migration in a dose- and time-dependent manner. Integrating in silico and in vitro evidence, we propose that morin primarily targets PIK3CA leading to modulation of the PI3K-Akt pathway, thereby contributing to reduced proliferation and migration of GC cells. Together, these findings highlight morin as a promising natural molecule with therapeutic potential against gastric cancer.