SHP2 suppressed the progression of IL-1β induced cartilage damage via modulating BRD4 associated autophagy and pyroptosis signaling pathway

To elucidate the protective mechanism of SHP2 in OA by targeting the BRD4/autophagy/apoptosis axis, focusing on its role in alleviating IL-1β-induced cartilage degradation and mitochondrial dysfunction. The OA- related mRNA dataset GSE82107 was first bioinformatically analyzed to identify differentially expressed genes (DEGs) and enrichment pathways using R language packages (limma, ggplot2) and the DAVID platform. In in vivo experiments, HE staining and Safranin O/Fast Green staining were used to detect the pathology of cartilage tissue. Transmission electron microscopy (TEM) was used to observe the mitochondrial ultrastructure in cartilage tissue. The expression of IL-1β, BRD4, p-NF-kB, p-SHP2, PINK1, LC-3I, Beclin, NLRP3 and GSDMD in cartilage tissues was detected using Western blot assay. Western blot assay was used to detect the expression of NOX4, PINK1, Beclin, p-STING, BRD4, p-SHP2, Bax, Caspase8, GSDMD and NLRP3 in chondrocytes. The relative fluorescence intensity of p-SHP2 in chondrocytes was detected by immunofluorescence staining assay. Flow cytometry was used to detect apoptosis in chondrocytes. Bioinformatics analysis revealed significant dysregulation of inflammatory response and autophagy pathways in OA. In in vivo experiments, HE staining and Safranin O/Fast Green staining analysis showed that SHP2 alleviated IL-1β-induced cartilage matrix degradation. Transmission electron microscopy showed that SHP2 reduced mitochondrial damage in cartilage tissues. Western blot experiments showed that SHP2 decreased the expression of IL-1β, BRD4, p-NF-kB, p-SHP2, NLRP3, and GSDMD, and increased the expression of PINK1, LC-3I, and Beclin in cartilage tissues. In in vitro experiments, chondrocytes were treated with IL-1β, and Western blot experiments showed that SHP2-mediated BRD4 decreased the expression of NOX4, p-STING, BRD4, p-SHP2, Bax, Caspase8, GSDMD. Expression of PINK1 and Beclin in chondrocytes. Immunofluorescence experiments showed that SHP2-mediated BRD4 signaling decreased the relative fluorescence intensity of p-SHP2 in chondrocytes. Flow cytometry analysis showed that SHP2-mediated BRD4 inhibited apoptosis in chondrocytes. SHP2 exerts chondroprotective effects in OA by regulating the BRD4/autophagy/apoptosis axis. Its activation maintains mitochondrial function and autophagy, whereas inhibition accelerates OA pathology. Targeting SHP2 represents a potential therapeutic strategy for the treatment of OA.