Exploring the Potential Mechanism of Isoliquiritigenin in the Treatment of Osteoarthritis through Integrated Network Pharmacology, Molecular Docking, and Experimental Validation.
INTRODUCTION Osteoarthritis (OA) is a prevalent and chronic joint disease characterized by progressive cartilage degeneration and chronic inflammation. Isoliquiritigenin (ISL), a bioactive flavonoid derived from licorice, has demonstrated significant anti-inflammatory potential in various diseases. However, its specific molecular targets and systemic mechanisms in the treatment of OA remain to be fully elucidated. This study aimed to investigate the potential targets and molecular mechanisms of ISL in OA treatment using an integrated pharmacological and experimental approach. METHODS Overlapping targets between ISL and OA were identified using multiple public databases. A PPI network was constructed to identify hub genes, followed by GO and KEGG enrichment analyses to predict key signaling pathways. A ceRNA regulatory network was also established. Furthermore, molecular docking was employed to assess the binding stability between ISL and core targets, and the findings were validated through histopathological evaluation (Mankin score) and RT-qPCR analysis in a rabbit ACLT-induced OA model. RESULTS A total of 79 shared targets were identified, from which 11 core targets were selected for further investigation. Enrichment analysis revealed that the therapeutic effects of ISL are primarily associated with the MAPK, PI3K-Akt, and mTOR signaling pathways, which are essential for maintaining chondrocyte homeostasis. Molecular docking indicated that ISL exhibits strong binding affinities (all binding energies < -5.0 kcal/mol) for the core targets. In vivo experiments confirmed typical cartilage degradation in the OA group, accompanied by significantly elevated Mankin scores. RT-qPCR results verified the significant differential expression of six core targets (IGF1R, PLAU, EGFR, PTGS2, PPARG, and GSK3B) in the OA cartilage, validating their involvement in OA pathogenesis. DISCUSSION In this study, we preliminarily determined the potential therapeutic effects of ISL on OA through its modulation of multiple targets and complex signaling pathways. The integration of network pharmacology and in vivo validation suggests that ISL may exert its anti-OA effects by targeting key inflammatory and metabolic mediators identified in our PPI and ceRNA networks. CONCLUSION ISL is predicted to have substantial potential for clinical application in OA treatment. These findings provide a novel theoretical foundation and specific candidate targets for future research into targeted therapeutic strategies for OA.