Abstract

OBJECTIVES This study aimed to identify key regulatory genes involved in chondrocyte senescence in osteoarthritis (OA) and to evaluate the therapeutic potential of the GLP-1 receptor agonist semaglutide. METHODS Transcriptomic data of chondrocytes from OA and control groups were collected. Batch effects were corrected using Harmony, and differential expression analysis was performed with DESeq2 to identify significantly altered genes. Functional enrichment and pathway involvement were assessed using KEGG and Gene Set Enrichment Analysis (GSEA). Weighted gene co-expression network analysis (WGCNA) was applied to identify OA-related modules, and protein-protein interaction (PPI) networks were constructed to screen for hub genes. In vitro experiments included ROS detection, RT-PCR, and ELISA to evaluate oxidative stress, inflammatory mediators, and senescence-associated gene expression. Cell proliferation was assessed using CCK-8, and semaglutide treatment at different concentrations was applied to verify its regulatory effects. RESULTS Transcriptomic analysis revealed significant upregulation of inflammatory and oxidative stress pathways in OA chondrocytes, accompanied by downregulation of cell cycle and DNA repair pathways, suggesting the accumulation of senescent cells. WGCNA and PPI network analyses identified GAPDH as a key hub gene, whose expression was markedly reduced in OA. In vitro validation confirmed decreased proliferative capacity, elevated ROS levels, and increased expression of p53, IL-6, and TGF-β in OA cells. Semaglutide treatment reversed GAPDH downregulation, improved proliferation, and reduced p53 and inflammatory cytokine levels, suggesting that it exerts protective effects through modulation of the glycolysis-senescence-inflammation axis. CONCLUSION