Cytotoxic and apoptotic effects of kaempferol 3-O-rhamnoside from Schima wallichii in HepG2 cells.

Schima wallichii (DC.) Korth is a medicinal plant with notable pharmacological potential but remains poorly characterized. In this study, the crude extract and solvent fractions from Schima wallichii leaves were evaluated for cytotoxic activity against various human cancer cell lines. Both the total extract and its fractions exhibited dose-dependent inhibitory effects on the proliferation of hepatocellular carcinoma HepG2 cells. From the most active fraction, a major flavonoid was isolated and identified as kaempferol-3-O-rhamnoside. In vitro assays revealed that kaempferol-3-O-rhamnoside effectively suppressed HepG2 cell growth and induced apoptosis by activating caspase-3, modulating cell cycle progression, and enhancing the expression of cleaved caspase-3 protein. Complementary in silico analyses showed that K3OR bound favorably to apoptosis-related targets, including caspase-3, caspase-8, caspase-9, and PARP-1, with strong hydrogen-bonding and π-π interactions at their catalytic sites. Molecular dynamics simulations confirmed the high structural stability of the kaempferol-3-O-rhamnoside-caspase 3 complex throughout a 100-ns trajectory, while density functional theory calculations indicated a moderate HOMO-LUMO energy gap (6.48 eV), semi-soft electronic nature, and a global electrophilicity index (ω = 3.18 eV), consistent with its favorable binding reactivity. These findings suggest that K3OR exerts cytotoxic effects through caspase-mediated apoptotic activation, providing mechanistic insight into its anti-proliferative activity in liver cancer cells.