ATG5-mediated cGAS-STING-NLRP3 axis alleviates symptoms of knee osteoarthritis.

Knee osteoarthritis (KOA) is a degenerative joint disorder characterized by articular cartilage degeneration and synovial inflammation. Dysfunction mediated by autophagy-related protein 5 (ATG5) represents a key driver of KOA pathogenesis, while the cGAS-STING-NLRP3 signaling axis is closely associated with inflammation and apoptosis. Therefore, this study aims to explore the regulatory effect of ATG5 on the cGAS-STING-NLRP3 axis and its specific role in KOA. HE staining, Safranin O-fast green staining were used to assess the degree of cartilage degeneration in KOA rats. TUNEL staining were applied to observe the apoptosis of chondrocytes in cartilage tissues. Levels of inflammatory factors in serum of rats and cells were detected by ELISA. Expression of proteins levels was analyzed using western blot and immunofluorescence assay. Flow cytometry was used to investigate the apoptosis. In cartilage tissues of KOA rats, ATG5 was lowly expressed, while cGAS, STING and NLRP3 were overexpressed. Co-localization was observed between ATG5 and STING. Overexpression of ATG5 led to decreased expression of inflammatory factors, cGAS, STING, NLRP3, p62 and Cleaved caspase-1, a reduced Mankin score, and increased Beclin1 expression. However, knockout of ATG5 reversed these changes. Additionally, overexpression of ATG5 decreased the apoptosis rate of chondrocytes, whereas inhibition of ATG5 promoted chondrocyte apoptosis. In conclusion, ATG5 regulates the cGAS-STING-NLRP3 axis, thereby promoting chondrocyte autophagy and inhibiting inflammation, which in turn protects chondrocytes and alleviates KOA. In conclusion, ATG5 modulates the cGAS-STING-NLRP3 axis, thereby enhancing chondrocyte autophagy and suppressing inflammation, which collectively protects chondrocytes and alleviates the progression of KOA.