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Polydatin-Mediated Inhibition of HSP90α Disrupts NLRP3 Complexes and Alleviates Acute Pancreatitis

Jiashu Yang1, Chenyang Jiao1, Nannan Liu1

  • 1State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China.

Research (Washington, D.C.)
|December 18, 2024
PubMed

Insights

Targeting HSP90α offers a new strategy for inflammatory diseases. Inhibiting HSP90α disrupts NLRP3 inflammasome stability, reducing activation and alleviating pancreatitis.

Area of Science:

  • Immunology
  • Molecular Biology
  • Drug Discovery

Background:

  • The NLRP3 inflammasome is central to inflammation but drug development has faced challenges.
  • Existing NLRP3 inhibitors like MCC950 show limited clinical success.
  • Certain NLRP3 forms and mutations are resistant to current inhibitors.

Purpose of the Study:

  • To investigate mechanisms of NLRP3 inflammasome activation and resistance.
  • To identify novel therapeutic targets for NLRP3-driven inflammatory diseases.
  • To evaluate the role of HSP90α in NLRP3 inflammasome stability and activation.

Main Methods:

  • Utilized small-molecule compound polydatin to probe NLRP3 interactions.
  • Investigated the interaction between HSP90α and NLRP3 complexes (resting and activated).
  • Employed genetic and pharmacological inhibition of HSP90α in disease models.

Main Results:

  • Activated NLRP3 inflammasome complexes and L351P mutation showed MCC950 resistance.
  • HSP90α stabilizes both resting (cage-NLRP3) and activated (disc-NLRP3) NLRP3.
  • Polydatin targets HSP90α, disrupting its interaction with NLRP3 and leading to complex dissipation.
  • HSP90α inhibition reduced NLRP3 activation and ameliorated acute pancreatitis in vivo.

Conclusions:

  • HSP90α is essential for NLRP3 inflammasome stability and sustained activation.
  • Targeting HSP90α is a promising therapeutic strategy for NLRP3-mediated inflammatory conditions.
  • HSP90α inhibition offers a potential solution for diseases where current NLRP3 drugs are ineffective.

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