Panobinostat suppresses cGAS-STING pathway activation and ameliorates DSS-induced colitis in mice

Area of Science:

• Immunology
• Molecular Biology
• Pharmacology

Background:

• The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in innate immunity by sensing nucleic acids.
• Aberrant activation of the cGAS-STING pathway leads to excessive cytokine production, resulting in inflammatory tissue damage, immune pathology, and autoimmune diseases, often linked to type I interferon release.

Purpose of the Study:

• To identify therapeutic strategies for inhibiting aberrant cGAS activation.
• To investigate the potential of epigenetic drugs, specifically histone deacetylase inhibitors, in modulating the cGAS-STING pathway.

Main Methods:

• Screening of an epigenetic drug library to identify modulators of the cGAS-STING pathway.
• Assessing the effect of identified compounds on mRNA expression and protein phosphorylation of inflammatory mediators.
• Evaluating the therapeutic efficacy of the lead compound in a mouse model of colitis.

Main Results:

• Panobinostat, a histone deacetylase inhibitor, was identified as a significant suppressor of the cGAS-STING pathway.
• Panobinostat reduced both mRNA expression and protein phosphorylation of downstream inflammatory mediators.
• Panobinostat decreased the secretion of inflammatory factors and alleviated symptoms in a mouse model of dextran sulfate sodium-induced colitis.

Conclusions:

• Inhibiting aberrant cGAS activation is a promising therapeutic strategy for inflammatory diseases.
• Panobinostat demonstrates significant potential in suppressing the cGAS-STING pathway and ameliorating inflammatory conditions.
• These findings offer new insights into the prevention and treatment of inflammatory diseases by targeting the cGAS-STING pathway.