Mechanistic Insights into LGALS3-Mediated Osteoarthritis Progression: Activation of the cGAS-STING Pathway as a Key Driver of Senescence-Related Osteoarthritis

This study investigates the role of LGALS3 overexpression in senescence-related osteoarthritis (OA) and elucidates the mechanism by which it activates the cGAS - STING pathway to promote cellular senescence and OA progression. Mendelian randomization analysis and RNA-seq data from the public GEO database were used to identify differential gene expression in knee joint samples from OA patients versus healthy controls. The expression of LGALS3 , cGAS , and STING , as well as senescence and OA-related indicators (including P53 and MMP3 ), were assessed using Western blotting and immunofluorescence labeling. In cell studies, chondrocytes were engineered to overexpress LGALS3 , and reactive oxygen species levels, mitochondrial activity, and cell senescence were evaluated using DCFH-DA staining, β-gal staining, and immunofluorescence methods. RNA-seq analysis from the GEO database revealed that LGALS3 expression was significantly elevated in OA chondrocytes. This finding was further validated by Mendelian randomization analysis. Functional experiments showed that LGALS3 overexpression activated the cGAS-STING pathway, upregulated P53 and MMP3 levels, increased intracellular reactive oxygen species accumulation, impaired mitochondrial function, accelerated cartilage degeneration, and promoted chondrocyte senescence (all p < 0.05). Overexpression of LGALS3 promotes chondrocyte senescence by activating the cGAS-STING pathway, and reduces mitochondrial activity in cells, thereby leading to osteoarthritis. These findings identify LGALS3 and the cGAS-STING pathway as potential therapeutic targets warranting further investigation in preclinical OA models.