2. Academic Validation
  3. CORM-3 mitigates osteoarthritis by anti-inflammation and enhancing autophagy via inhibiting MAPK and mTOR pathways

CORM-3 mitigates osteoarthritis by anti-inflammation and enhancing autophagy via inhibiting MAPK and mTOR pathways

  • Int Immunopharmacol. 2025 Jul 31:163:115296. doi: 10.1016/j.intimp.2025.115296.
Jianwen Li 1,  Yunqian Zeng 2,  Shiheng Wang 3,  Xin Chen 4,  Hui Huang 5,  Xin Gan 6,  Hao Kang 7
Affiliations

Affiliations

  • 1 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: d202282265@hust.edu.cn.
  • 2 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: m202176390@hust.edu.cn.
  • 3 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: m202476708@hust.edu.cn.
  • 4 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: m202276376@hust.edu.cn.
  • 5 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: 2011tj0650@hust.edu.cn.
  • 6 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: d202282263@hust.edu.cn.
  • 7 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: 2010tj0625@hust.edu.cn.
PMID: 40749610 DOI: 10.1016/j.intimp.2025.115296
Abstract

Background: Osteoarthritis (OA) is a chronic degenerative disorder marked by progressive degradation of articular cartilage. Inflammation and impairment of Autophagy are crucial in OA pathogenesis, leading to chondrocyte dysfunction and disease progression. The therapeutic potential of CORM-3, a carbon monoxide-releasing molecule with anti-inflammatory and autophagy-enhancing properties, remains unexplored in OA.

Methods: Chondrocytes were treated with interleukin-1β (IL-1β) to establish an inflammatory model in vitro. The impact of CORM-3 on chondrocyte inflammation, extracellular matrix (ECM) metabolism, and Autophagy activity was assessed by RT-qPCR, Western blot, immunofluorescence, and Autophagy flow assay. OA was induced in mice to investigate CORM-3's therapeutic potential in vivo through surgical destabilization of the medial meniscus (DMM).

Results: CORM-3 significantly inhibited the inflammation of chondrocytes and the imbalance of extracellular matrix (ECM) metabolism induced by IL-1β, thereby exerting a chondroprotective effect in vitro. Mechanistically, CORM-3 effectively inhibited the mitogen-activated protein kinase (MAPK) and mTOR signaling pathways. Further, CORM-3 exerted a similar chondroprotective effect with MAPK-IN-1, a MAPK pathway inhibitor, and rapamycin, a specific mTOR Inhibitor. Additionally, CORM-3 also restored the impairment of Autophagy. Furthermore, 3-Methyladenine (3-MA), an Autophagy inhibitor, reversed CORM-3's chondroprotective effect. In vivo, treatment with CORM-3 inhibited cartilage OA-like lesions to mitigate OA progression.

Conclusion: This study identifies that CORM-3 inhibits inflammation, maintains ECM metabolism homeostasis, and restores impaired Autophagy via inhibiting the MAPK and mTOR pathways, thereby protecting chondrocytes. In vivo, CORM-3 treatment significantly alleviates OA progression, suggesting its therapeutic potential for OA.

Keywords

Autophagy; CORM-3; Inflammation; MAPK; Osteoarthritis; mTOR.

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