Mechanistic Insights Into Celastrol's Anti-Pyroptosis Effects in Osteoarthritis via SIRT2 Upregulation

Background: Chronic inflammation and cell apoptosis are hallmark characteristics of osteoarthritis (OA), necessitating the development of novel therapeutic strategies. Celastrol (CSL) has emerged as a promising agent for OA treatment due to its anti-inflammatory properties, but the specific mechanism of action remains unclear. Methods: This study utilized network pharmacology and in vivo experiments to elucidate how CSL modulates the SIRT2-NLRP3 axis in OA. Chondrocytes were treated with CSL to evaluate changes in SIRT2 expression and NLRP3 acetylation levels. OA rats were administered CSL to assess its therapeutic effects. Results: Using network pharmacology and bioinformatics, SIRT2 and NLRP3 were identified as the primary therapeutic targets of CSL for OA. In vitro experiments demonstrated that CSL significantly reduced the levels of inflammatory markers and pyroptosis-related proteins, such as GSDMD-N, in TC28a cells and primary rat chondrocytes (RCs) induced by lipopolysaccharide (LPS) and nigericin (Nig). CSL upregulated SIRT2 expression, decreased NLRP3 acetylation, and promoted anti-inflammatory cytokine expression (IL-4 and IL-10), thereby, reducing inflammation and pyroptosis in chondrocytes. Notably, SIRT2 knockdown reversed CSL's anti-inflammatory and anti-pyroptosis effects. In vivo, CSL significantly alleviated OA symptoms in rats by modulating the SIRT2/NLRP3 pathway. Conclusion: CSL exerts its anti-inflammatory effects in OA by targeting the SIRT2-NLRP3 axis to inhibit chondrocyte pyroptosis. These findings underscore the potential of CSL as a therapeutic agent for mitigating OA progression and offer new insights into its molecular mode of action.