Mechanism of Morin in Inhibiting Gastric Cancer Cells via Regulation of the PI3K/Akt Pathway

• • Morin at 100–400 μmol/L dose-dependently inhibited AGS cell proliferation (P<0.05, 0.01), with an IC50 of 214.28 μmol/L in HeLa cells, indicating moderate potency but favorable safety (no adverse effects at 300 mg/kg daily in animals). This positions morin as a low-toxicity alternative to synthetic PI3K inhibitors like LY294002, which suffer from poor solubility and off-target effects. • • Morin induced G0/G1 phase arrest and apoptosis, reducing G2/M phase cells, and downregulated PI3K/Akt pathway proteins (p85α, p110β, p-Akt) and cell cycle regulators (Bcl-2, CCND1, CDK4, CDK6) while upregulating Bax and p21 (P<0.05, 0.01). These molecular changes directly correlate with inhibition of malignant proliferation, offering a multi-target mechanism that may overcome resistance to single-target therapies. • • The PI3K agonist 740Y-P significantly reversed morin's anti-proliferative, pro-apoptotic, and cell cycle arrest effects (P<0.05, 0.01), confirming that morin's activity is mediated through PI3K/Akt pathway suppression. This validation provides a mechanistic basis for targeting PIK3R1, which is overexpressed in gastric cancer (GSE54129 dataset), as a therapeutic strategy. • • Molecular docking and dynamics simulations demonstrated high affinity and stable binding between morin and PIK3R1, with the complex maintaining structural integrity. This supports PIK3R1 as a direct target, distinguishing morin from other flavonoids and underscoring its potential for development as a PIK3R1-specific inhibitor with improved pharmacokinetics over wortmannin and LY294002.