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CREG1 Attenuates Osteoarthritis Progression by Suppressing Chondrocyte Pyroptosis Through the PINK1/Parkin-Mediated

Xianming Fei1, Shuanggong Liu2, Guangxu Song2

  • 1Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

Biotechnology Journal
|February 16, 2026
PubMed
Abstract

Insights

Cellular repressor of E1A-stimulated gene 1 (CREG1) protects against osteoarthritis (OA) by reducing chondrocyte pyroptosis. CREG1 enhances mitophagy and mitochondrial function, offering a potential therapeutic target for OA.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pathology

Background:

  • Osteoarthritis (OA) is a degenerative joint disease where chondrocyte pyroptosis, mediated by the NLRP3 inflammasome, is a key driver of progression.
  • Cellular repressor of E1A-stimulated gene 1 (CREG1), a glycoprotein regulating cellular homeostasis, has an uncharacterized role in OA pathogenesis.

Purpose of the Study:

  • To investigate the role and molecular mechanisms of CREG1 in osteoarthritis.
  • To determine if CREG1 influences NLRP3 inflammasome-mediated chondrocyte pyroptosis.

Main Methods:

  • Analysis of human OA cartilage to correlate CREG1 expression with chondrocyte pyroptosis.
  • Utilizing an in vitro model of LPS/ATP-induced chondrocyte pyroptosis to assess CREG1's effects on apoptosis, extracellular matrix (ECM) degradation, NLRP3 inflammasome activation, and mitophagy (PINK1/Parkin-dependent).
  • Employing Cyclosporin A (CsA) to inhibit mitophagy and evaluate its impact.

Main Results:

  • CREG1 expression was significantly decreased in OA cartilage and inversely correlated with chondrocyte pyroptosis.
  • CREG1 silencing exacerbated apoptosis, ECM degradation, NLRP3 inflammasome activation, and impaired mitophagy and mitochondrial function.
  • CREG1 overexpression reversed these detrimental effects by restoring mitophagy, improving mitochondrial homeostasis, and suppressing NLRP3 inflammasome activation, effects blocked by CsA.

Conclusions:

  • CREG1 acts as a protective factor against OA progression by inhibiting NLRP3 inflammasome-driven chondrocyte pyroptosis.
  • CREG1 achieves this protection via the activation of PINK1/Parkin-dependent mitophagy.
  • CREG1 represents a promising therapeutic target for osteoarthritis treatment.
Keywords:
CREG1NLRP3 inflammasomemitophagyosteoarthritispyroptosis

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