Piperine inhibits NLRP3 inflammasome activation and alleviates inflammatory disease

  • Phytomedicine. 2026 Jun 17:159:158448. doi: 10.1016/j.phymed.2026.158448.
Rui Guo  1 ,  Zhiqiang Niu  2 ,  Feng Chen  3 ,  Lingjun Zheng  4 ,  Junyao Li  2 ,  Luyao Qi  2 ,  Guiping Wu  5 ,  Xu Wang  6 ,  Fei Xu  5 ,  Jae Youl Cho  7 ,  Weicheng Hu  8 ,  Hongying Zhu  9 ,  Fenglin Gu  10
Affiliations
  • 1. Spice and Beverage Research Institute, Chinese Academy of Tropical Agricultural Sciences/Key Laboratory of Processing Suitability and Quality Control of the Special Tropical Crops of Hainan Province/National Center of Important Tropical Crops Engineering and Technology Research, Wanning 571533, Hainan, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China; School of Basic Medical Sciences, Faculty of Medicine, Yangzhou University, Yangzhou 225009, China.
  • 2. School of Basic Medical Sciences, Faculty of Medicine, Yangzhou University, Yangzhou 225009, China.
  • 3. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China; School of Chemistry and Materials, Yangzhou University, Yangzhou 225002, China.
  • 4. School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 5. Spice and Beverage Research Institute, Chinese Academy of Tropical Agricultural Sciences/Key Laboratory of Processing Suitability and Quality Control of the Special Tropical Crops of Hainan Province/National Center of Important Tropical Crops Engineering and Technology Research, Wanning 571533, Hainan, China.
  • 6. Spice and Beverage Research Institute, Chinese Academy of Tropical Agricultural Sciences/Key Laboratory of Processing Suitability and Quality Control of the Special Tropical Crops of Hainan Province/National Center of Important Tropical Crops Engineering and Technology Research, Wanning 571533, Hainan, China; Sanya Research Institute, Chinese Academy of Tropical Agricultural Sciences, Sanya 572025, Hainan, China.
  • 7. Department of Integrative Biotechnology, and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, South Korea.
  • 8. School of Basic Medical Sciences, Faculty of Medicine, Yangzhou University, Yangzhou 225009, China. Electronic address: [email protected].
  • 9. Spice and Beverage Research Institute, Chinese Academy of Tropical Agricultural Sciences/Key Laboratory of Processing Suitability and Quality Control of the Special Tropical Crops of Hainan Province/National Center of Important Tropical Crops Engineering and Technology Research, Wanning 571533, Hainan, China. Electronic address: [email protected].
  • 10. Spice and Beverage Research Institute, Chinese Academy of Tropical Agricultural Sciences/Key Laboratory of Processing Suitability and Quality Control of the Special Tropical Crops of Hainan Province/National Center of Important Tropical Crops Engineering and Technology Research, Wanning 571533, Hainan, China; Sanya Research Institute, Chinese Academy of Tropical Agricultural Sciences, Sanya 572025, Hainan, China. Electronic address: [email protected].
PMID: 42364560 DOI: 10.1016/j.phymed.2026.158448
Abstract

Background: Excessive or aberrant activation of the NLRP3 inflammasome is implicated in the initiation and progression of various inflammatory diseases.

Purpose: This study aimed to investigate whether piperine (PIP) inhibited NLRP3 inflammasome activation and disrupting the NEK7-NLRP3 interaction, and to evaluate its anti-inflammatory effects in vivo.

Methods: We identified NLRP3 as a potential target of PIP through COMET database and RNA Sequencing. A classic NLRP3 inflammasome activation model was established in immortalized bone marrow-derived macrophages (iBMDMs) primed with lipopolysaccharide (LPS) and then activated with nigericin. Protein interactions and binding modes were analyzed using co-immunoprecipitation and molecular modeling. The protective effects of PIP were evaluated in mouse models of acute lung injury and colitis.

Results: PIP effectively inhibited NLRP3 inflammasome activation without affecting NLRC4 or AIM2 inflammasome. Furthermore, PIP blocked NLRP3 protein oligomerization and ASC recruitment, and inhibited inflammasome assembly by interfering with NEK7-NLRP3 interaction. Molecular simulation confirmed that PIP binds noncovalently to NLRP3 at lysine 232 via a hydrogen bond, and mutating this residue to alanine eliminated its inhibitory effect on the NEK7-NLRP3 interaction. In vivo, PIP markedly alleviated LPS-induced acute lung injury and dextran sulfate sodium-induced colitis by reducing inflammatory responses.

Conclusion: These findings demonstrate that PIP inhibited NLRP3 inflammasome activation by targeting Lys232 and exerted potent anti-inflammatory effects in vivo, supporting its potential as a therapeutic candidate for NLRP3-driven inflammatory diseases.

Keywords
Acute lung injury; Colitis; NLRP3; Piperine; Target discovery.
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