Discovery of Semiliquidambar cathayensis and its parent species as potent anti-osteoarthritic agents through integrated in vitro, in vivo and network pharmacological analyses

The increasing global prevalence of osteoarthritis (OA) underscores the urgent need for safer alternatives to existing therapies. Semiliquidambar cathayensis (SC) and its two parent species, Altingia chinensis (AC) and Liquidambar formosana (LF), have been traditionally employed to treat inflammatory conditions, yet they remain insufficiently studied in modern pharmacology. This study evaluated their anti-OA mechanisms through integrated in vitro, in vivo, and network pharmacology approaches to develop natural anti-osteoarthritic agents. The extracts of these three species potently inhibited NO and ROS production (P < 0.01) at 7.8125 μg/mL in LPS-stimulated Raw264.7 macrophages. LC-MS, network pharmacology, molecular docking, and molecular dynamics simulation identified six key compounds (3,3′,4-tri-O-methylellagic acid, galbacin, gallic acid, loliolide, trans-resveratrol 3-O-β-glucoside, and prenylcaffeate) interacting with the PI3K/Akt/NF-κB pathway from these three plants. Notably, trans-resveratrol 3-O-β-glucoside surpassed dexamethasone in inhibiting NO/ROS. In vivo assays revealed that all extracts ameliorated apoptosis, proteoglycan loss, and cartilage degradation in MIA-induced rats, with comparable efficacy (P > 0.05) among species. Specifically, all of the extracts reduced the expression of inflammatory markers (IκB, IL-6, TNF-α, iNOS, p65) and promoted cartilage repair, as confirmed by histological and immunohistochemical analysis. This study provides the first pharmacological validation of SC, AC, and LF as potent anti-osteoarthritic agents through modulation of the PI3K/Akt/NF-κB pathway and suppression of oxidative stress, with trans-resveratrol 3-O-β-glucoside identified as a highly potent bioactive component within these three species. Their equivalent efficacy supports AC and LF as sustainable substitutes, alleviating conservation pressure on SC.