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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
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Heat shock protein 90 inhibitors suppress pyroptosis in THP-1 cells

Zhou Zhou1, Xiuzhen Li1,2, Yisong Qian1,3

  • 1Department of Biomedical Science, School of Medicine, University of Missouri Kansas City, 2411 Holmes Street, Kansas City, MO 64108, U.S.A.

The Biochemical Journal
|June 5, 2020
PubMed

Insights

Small chemicals that reduce pyroptosis, a form of inflammatory cell death, were identified. HSP90 inhibitors, like Geldanamycin, effectively suppressed pyroptosis by targeting the inflammasome pathway, offering potential therapeutic strategies for inflammatory diseases.

Area of Science:

  • Immunology
  • Cell Biology
  • Pharmacology

Background:

  • Pyroptosis is an inflammatory cell death pathway often triggered by pathogens.
  • It plays a significant role in inflammatory diseases.
  • Targeting pyroptosis presents a potential therapeutic avenue, but effective small molecules are needed.

Purpose of the Study:

  • To identify small chemicals that can mitigate pyroptosis.
  • To investigate the mechanism by which identified compounds affect pyroptosis.
  • To explore the therapeutic potential of inhibiting pyroptosis.

Main Methods:

  • Screening of 155 microbial natural products.
  • Utilizing THP-1 cell models to induce and measure pyroptosis (LPS plus Nigericin).
  • Assessing the effects of HSP90 inhibitors on the inflammasome/Caspase-1/GSDMD pathway and NLRP3 stability.

Main Results:

  • Geldanamycin, an HSP90 inhibitor, significantly protected THP-1 cells from pyroptosis.
  • Other HSP90 inhibitors (Radicicol, 17-DMAG, 17-AAG) also ameliorated pyroptosis.
  • HSP90 inhibition reduced NLRP3 protein stability and suppressed the inflammasome pathway.

Conclusions:

  • HSP90 inhibition is a promising strategy to mitigate pyroptosis.
  • Targeting HSP90 may offer a novel therapeutic approach for inflammatory diseases.
  • The mechanism involves compromising NLRP3 stability and suppressing key inflammasome components.
Keywords:
NLRP3THP-1gasdemin Dinflammasomepyroptosis

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