D-aring to explore: New approaches to gasdermin D targeting

Area of Science:

• Biochemistry
• Pharmacology
• Immunology

Background:

• Pyroptosis is an inflammatory cell death pathway implicated in various diseases, including cancer and inflammatory conditions.
• Current inhibitors often have off-target effects, limiting their therapeutic potential.
• Gasdermin D (GSDMD) is a key executioner protein in pyroptosis.

Purpose of the Study:

• To identify novel therapeutic agents that can selectively inhibit pyroptosis.
• To investigate the potential of repurposed drugs for targeting gasdermin D (GSDMD) oligomerization.

Main Methods:

• Drug screening and repurposing.
• Biochemical assays to assess GSDMD oligomerization.
• Cell-based assays to measure pyroptosis inhibition.
• Evaluation of off-target effects.

Main Results:

• Two repurposed drugs were identified that effectively inhibit gasdermin D (GSDMD) oligomer formation.
• These drugs demonstrated selective suppression of pyroptosis.
• Reduced off-target effects compared to traditional cysteine-based inhibitors were observed.

Conclusions:

• Repurposed drugs targeting gasdermin D (GSDMD) oligomers represent a promising therapeutic avenue for inflammatory diseases and malignant tumors.
• Selective inhibition of pyroptosis with reduced side effects is achievable.
• This study provides a foundation for developing new pyroptosis-targeting therapies.