MOTS-c attenuates mitochondrial dysfunction induces pyroptosis and cartilage degradation in osteoarthritis via an Nrf2-Dependent Mechanism

  • Free Radic Biol Med. 2025 Oct 1:241:717-731. doi: 10.1016/j.freeradbiomed.2025.09.056.
Kechi Li  1 ,  Tao Yang  2 ,  Feiyu Chen  3 ,  Chao Lou  4 ,  Yanlin Chen  5 ,  Zhenzhong Chen  6 ,  Lin Ye  7 ,  Xiaolong Sun  8 ,  Guoxiang Liu  9 ,  Chenglong Xie  10 ,  Jiawei Fang  11 ,  Xingyu Hu  12 ,  Ye Zhu  13 ,  Bin Liu  14 ,  Dengwei He  15 ,  Haiwei Ma  16
Affiliations
  • 1. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 2. Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Orthopedic Department, Taizhou Hospital Affiliated to Wenzhou Medical University, Enze Medical Research Center, Linhai, China. Electronic address: [email protected].
  • 3. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 4. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 5. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 6. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 7. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 8. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 9. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 10. Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 11. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 12. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 13. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 14. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 15. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
  • 16. The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang Province, China. Electronic address: [email protected].
PMID: 41043625 DOI: 10.1016/j.freeradbiomed.2025.09.056
Abstract

Osteoarthritis, a common chronic degenerative disease in the field of orthopedics, is caused by the interaction of mechanical stress, traumatic inflammation, and metabolic imbalance, and this interaction progresses over time. MOTS-c, a mitochondria-derived peptide, exerts pivotal roles in regulating metabolism, anti-inflammation, and antioxidant stress responses. However, current research on the role of MOTS-c in osteoarthritis remains scarce, and its specific mechanism of action remains unclear. Therefore, this study aims to further explore the molecular mechanisms by which MOTS-c regulates osteoarthritis. Exogenous supplementation of MOTS-c improves mitochondrial dysfunction, inhibits the activation of inflammatory bodies and rescues chondrocyte Pyroptosis, thereby regulating the metabolic balance of extracellular matrix (ECM). Mechanistically, MOTS-c plays a key role in LPS-induced oxidative stress and chondrocyte Pyroptosis through the Nrf2/TXNIP/NLRP3 axis. Our research demonstrates that MOTS-c can not only effectively inhibit the expression of inflammatory factors but also promote the expression of major components of the extracellular matrix (ECM) and suppress the production of Matrix Metalloproteinases. We validated the in vivo efficacy of MOTS-c by establishing a murine osteoarthritis model. Analysis of imaging and histopathological results revealed that MOTS-c can effectively delay the degeneration of articular cartilage and ameliorate the progression of osteoarthritis. Collectively, our findings uncover the intrinsic regulatory mechanism of MOTS-c in chondrocytes and its potential value in the treatment of osteoarthritis.

Keywords
MOTS-c; Mitochondrial function; NLRP3; Nrf2; Osteoarthritis; Pyroptosis.
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