CREG1 Attenuates Osteoarthritis Progression by Suppressing Chondrocyte Pyroptosis Through the PINK1/Parkin‐Mediated Mitophagy Pathway

BACKGROUND: Osteoarthritis (OA) is a progressive degenerative disorder driven by complex pathogenic mechanisms. Increasing evidence indicates that NLRP3 inflammasome-mediated chondrocyte pyroptosis contributes critically to OA progression. Cellular repressor of E1A-stimulated gene 1 (CREG1), a secreted glycoprotein involved in cellular homeostasis and lysosomal function, has not been well characterized in OA. This study aimed to investigate the role of CREG1 in OA and its underlying molecular mechanisms. METHODS: Human knee OA cartilage samples were analyzed to evaluate the association between CREG1 expression and chondrocyte pyroptosis. An LPS/ATP-induced in vitro pyroptosis model was used to assess the effects of CREG1 on chondrocyte apoptosis, extracellular matrix (ECM) degradation, NLRP3 inflammasome activation, and PINK1/Parkin-dependent mitophagy. Cyclosporin A (CsA) was applied to inhibit mitophagy. RESULTS: CREG1 expression was significantly reduced in OA cartilage and negatively correlated with chondrocyte pyroptosis. CREG1 silencing aggravated apoptosis and ECM degradation, promoted NLRP3 inflammasome activation, impaired mitophagy, and disrupted mitochondrial function. Conversely, CREG1 overexpression restored PINK1/Parkin-mediated mitophagy, improved mitochondrial homeostasis, and suppressed NLRP3 inflammasome activation. These effects were abolished by CsA treatment. CONCLUSIONS: CREG1 protects against OA progression by suppressing NLRP3 inflammasome-driven chondrocyte pyroptosis through activation of PINK1/Parkin-dependent mitophagy, highlighting CREG1 as a potential therapeutic target.