2. Academic Validation
  3. Urolithin a attenuates rheumatoid arthritis by inhibiting inflammation and pyroptosis in fibroblasts via the AMPK/ NF-κB signaling pathway

Urolithin a attenuates rheumatoid arthritis by inhibiting inflammation and pyroptosis in fibroblasts via the AMPK/ NF-κB signaling pathway

  • Int Immunopharmacol. 2025 May 16:155:114604. doi: 10.1016/j.intimp.2025.114604.
Hao Chen 1,  Zhen Zhang 2,  Congcong Lu 3,  Yi Ding 1,  Zhengao Huang 3,  Maoqiang Li 4,  Liulong Zhu 5
Affiliations

Affiliations

  • 1 Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China.
  • 2 Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China. Electronic address: zhangzhen9714@zju.edu.cn.
  • 3 The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou 310006, China.
  • 4 Department of Orthopedic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China. Electronic address: limaoqiangzhong@126.com.
  • 5 Department of Orthopedic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China. Electronic address: zhuliulong@zju.edu.cn.
PMID: 40215775 DOI: 10.1016/j.intimp.2025.114604
Abstract

Urolithin A (UA), a metabolite of natural Polyphenols produced by the gut microbiota, alleviates the symptoms of rheumatoid arthritis (RA) by inhibiting the inflammatory response. UA alleviates the clinical symptoms of RA by inhibiting the occurrence of an inflammatory response, but the specific regulatory mechanism remains unclear. In this study, we established a CIA model in 8-week-old DBA mice and chose LPS-stimulated NIH/3 T3 cells to explore the effects of UA and attempted to elucidate its potential mechanisms. Our results showed UA significantly reduced arthritis scores, and inhibited inflammation, pannus formation, and cartilage and bone destruction of inflamed joints in CIA mice. In vitro, UA inhibited LPS-induced migration and proliferation, and alleviated NLRP3-mediated Pyroptosis, significantly inhibiting the protein expression levels of NLRP3, N-terminal gasdermin D, interleukin-1β, Caspase-1, and ASC in NIH/3T3 cells. A mechanistic investigation revealed that LPS enhanced phosphorylation of NF-κB and downregulated that of AMPK, which were categorically counteracted by UA treatment. Therefore, UA represents a new class of promising RA treatments targeting fibroblasts, widening the therapeutic options for RA.

Keywords

NF-κB; NLRP3 inflammasome; Urolithin A; fibroblast; pyroptosis; rheumatoid arthritis.

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