Arctigenin from Saussurea medusa Maxim. Targets the PI3K/AKT Pathway to Inhibit Hepatocellular Carcinoma Proliferation and Induces Apoptosis

Background: Hepatocellular carcinoma (HCC) is a highly lethal malignancy with limited therapeutic options. Arctigenin (ARC), a natural lignan derived from Saussurea medusa, exhibits anti-cancer activity, but its mechanism against HCC remain incompletely elucidated. Methods: This study integrated network pharmacology, molecular docking, molecular dynamics, in vitro, and in vivo experiments to investigate ARC’s anti-HCC effects. Results: Seventy-five potential targets shared between ARC and HCC were identified, with KEGG analysis highlighting the PI3K/AKT pathway as central. ARC showed strong binding to key proteins, and molecular dynamics indicated stable interactions with PIK3CA and GSK3B. In HepG2 cells, ARC inhibited proliferation in a dose- and time-dependent manner (IC50: 11.17 μM at 24 h, 4.888 μM at 48 h), induced apoptosis at high concentrations, suppressed PIK3CA phosphorylation, and increased GSK3B (Ser9) phosphorylation. In H22 tumor-bearing mice, ARC dose-dependently inhibited tumor growth (high dose: 50.6% vs. 63.0% for CTX) with minimal weight loss. Conclusions: These findings suggest ARC suppresses HCC by modulating the PI3K/AKT pathway, providing evidence for its development as a plant-derived therapeutic agent.