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High-Throughput Screening Reveals That CeeNU Acts as a New NLRP3 Inflammasome Inhibitor
Sen-Lin Ji1,2,3,4, Peipei Chen1,2,3,4, Huaiping Tang1,2,3,4
1Department of Neurology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University Nanjing China.
Abstract:
Pyroptosis is a special form of cell death that often occurs during excessive inflammation and injury, leading to tissue damage, disease progression, and other related issues. The Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an important regulatory factor in cellular pyroptosis that promotes the inflammatory response. Inhibitors targeting the NLRP3 inflammasome have emerged as promising potential therapeutic agents for inflammatory diseases. Through large-scale screening, we found that the FDA-approved drug CeeNU strongly inhibited NLRP3-mediated pyroptosis. CeeNU exhibited dose-dependent suppression of NLRP3 inflammasome activation and effectively mitigated inflammasome-driven pyroptotic cell death in both human and murine macrophages/microglia. Mechanistically, we further demonstrated that CeeNU specifically binds to arginine 335 within the NACHT domain of NLRP3, abrogating NLRP3 inflammasome activation by blocking its assembly. Importantly, CeeNU showed remarkable protective effects in multiple mouse models of NLRP3 inflammasome-mediated diseases, including experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG), lipopolysaccharide (LPS)-induced septic shock, monosodium urate (MSU)-induced peritonitis, and MSU-induced gouty arthritis. Our results demonstrate that CeeNU, a clinically available drug, acts as an NLRP3 inhibitor and holds therapeutic potential for NLRP3 inflammasome-mediated pyroptotic diseases.
Insights
CeeNU, an FDA-approved drug, effectively inhibits NLRP3 inflammasome activation and pyroptosis. This discovery offers therapeutic potential for inflammatory diseases driven by NLRP3 inflammasome signaling.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Pyroptosis, a form of inflammatory cell death, contributes to tissue damage and disease progression.
- The NLRP3 inflammasome is a key regulator of pyroptosis and inflammatory responses.
- Targeting the NLRP3 inflammasome presents a therapeutic strategy for inflammatory conditions.
Purpose of the Study:
- To identify inhibitors of NLRP3 inflammasome-mediated pyroptosis.
- To investigate the therapeutic potential of FDA-approved drugs for NLRP3-driven diseases.
Main Methods:
- Large-scale drug screening to identify NLRP3 inflammasome inhibitors.
- In vitro studies using human and murine macrophages/microglia to assess pyroptosis inhibition.
- In vivo studies using mouse models of NLRP3 inflammasome-mediated diseases.
Main Results:
- CeeNU was identified as a potent inhibitor of NLRP3 inflammasome activation and pyroptosis.
- CeeNU demonstrated dose-dependent suppression of inflammasome activity and pyroptotic cell death.
- CeeNU specifically binds to NLRP3, blocking its assembly and activation.
- CeeNU provided significant protection in mouse models of EAE, septic shock, peritonitis, and gouty arthritis.
Conclusions:
- CeeNU acts as a specific NLRP3 inflammasome inhibitor.
- CeeNU exhibits therapeutic potential for a range of NLRP3 inflammasome-mediated inflammatory diseases.
