• Physcion exhibits no significant cytotoxicity in RAW264.7 and C3H10T1/2 cells at concentrations up to 60 µmol/L.
• Physcion suppresses osteoclast differentiation by downregulating key genes (Acp5, CTSK, DC-STAMP, Nfatc1) without affecting osteoblast differentiation.
• Network pharmacology and molecular docking identify PI3K-AKT as a critical pathway, with strong binding to AKT1.
• Physcion reduces the p-AKT/AKT ratio during osteoclast differentiation, indicating its mechanism of action.