Astragaloside IV Alleviates Osteoarthritis by Upregulating ETS2: A Bioinformatics and Experimental Study.

Background: Osteoarthritis (OA) is a common degenerative joint disorder and there are currently no effective therapies to impede its destructive progression. Astragaloside IV (AS-IV), a natural compound, exhibits promising chondroprotective effects, yet its specific molecular mechanisms remain poorly clarified. Thus, this study employed transcriptomic profiling combined with bioinformatics analysis to identify OA-related characteristic genes, and further conducted experiments to verify the potential therapeutic mechanism of AS-IV. Methods: Analysis of the GSE114007 dataset was performed using False Discovery Rate (FDR)-adjusted Results: We identified 1548 differentially expressed genes (DEGs) primarily enriched in the extracellular matrix, with PI3K-Akt signaling closely related to OA. The MEBlack module was strongly associated with OA (cor = -0.79, p<0.0001). GSEA showed the feature genes were associated with the adipocytokine signaling pathway and glycosaminoglycan biosynthesis. Furthermore, molecular docking and CETSA indicated that ETS2 served as a potential interacting target of AS-IV. In the destabilization of the medial meniscus (DMM)-induced OA mice, the results of Safranin O/Fast Green staining confirmed that AS-IV alleviated cartilage loss and lowered OARSI scores. Mechanistically, AS-IV slowed OA progression by upregulating Col2a1 expression, suppressing MMP13 levels, and reducing inflammatory markers such as IL-1β and TNF-α. Importantly, AS-IV enhanced ETS2 expression in osteoarthritic chondrocytes. Consistently, in vitro functional assays revealed that knockdown of ETS2 in chondrogenic ATDC-5 cells partially reversed both the chondroprotective and anti-inflammatory effects of AS-IV, verifying the essential role of ETS2 in mediating the therapeutic effects of AS-IV against OA. Conclusion: Collectively, these findings point to the vital function of ETS2 in OA pathogenesis and demonstrate that AS-IV attenuates cartilage degradation and inflammatory responses by upregulating ETS2, thereby retarding OA development.