Kurarinone Alleviates cGAS-STING-Triggered Inflammatory Diseases by Targeting STING

Area of Science:

• Immunology
• Pharmacology
• Molecular Biology

Background:

• Aberrant activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is central to various inflammatory diseases.
• Kurarinone, a flavonoid from Sophorae tonkinensis Radix et Rhizoma, possesses known anti-inflammatory properties but its effect on the cGAS-STING pathway is underexplored.

Purpose of the Study:

• To investigate Kurarinone's impact on cGAS-STING pathway activation.
• To evaluate Kurarinone's protective effects against STING-mediated inflammatory conditions.

Main Methods:

• In vitro studies using BMDMs and THP-1 cells stimulated with STING agonists.
• Western blotting, ELISA, qPCR, nucleocytoplasmic separation, STING oligomerization assays, cellular thermal shift assays, drug affinity responsive target stability assays, and molecular docking.
• In vivo evaluation using DSS-induced inflammatory bowel disease and ConA-induced autoimmune hepatitis models.

Main Results:

• Kurarinone inhibited STING and IRF3 phosphorylation, reduced IFNβ release, and downregulated inflammatory cytokine transcription.
• It suppressed IRF3 nuclear translocation and disrupted STING-IRF3 interaction without affecting STING oligomerization.
• Kurarinone targeted STING, reducing its stability and enhancing degradation, and ameliorated disease severity in vivo.

Conclusions:

• Kurarinone directly targets STING, inhibiting the cGAS-STING pathway by interfering with STING-IRF3 interaction.
• Kurarinone demonstrates therapeutic potential for STING-driven inflammatory diseases, including inflammatory bowel disease and autoimmune hepatitis.