Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases

Area of Science:

• Immunology
• Pharmacology
• Computational Biology

Background:

• STING pathway activation is crucial for innate immunity but drives inflammatory diseases.
• Developing STING inhibitors faces challenges due to complex activation steps and traditional drug screening limitations.
• Targeting STING offers a therapeutic strategy for various inflammatory conditions.

Purpose of the Study:

• To identify novel STING inhibitors using a sequence-based AI model.
• To investigate the mechanism of action of Licochalcone D (LicoD) as a STING inhibitor.
• To evaluate the therapeutic potential of LicoD in preclinical models of STING-related diseases.

Main Methods:

• Utilized a TransformerCPI model for structure-independent compound screening against STING.
• Identified Licochalcone D (LicoD) as a potent STING inhibitor.
• Investigated LicoD's covalent modification of STING at Cys148 and its downstream effects on signaling pathways.
• Assessed LicoD efficacy in Trex1^-1- mice, DSS-induced colitis, and AOM/DSS-induced colitis-associated colon cancer models.

Main Results:

• LicoD acts as a potent and selective STING inhibitor by covalently modifying Cys148, independent of the classical ligand-binding pocket.
• LicoD inhibits STING oligomerization, TBK1 recruitment, and IRF3/NF-κB nuclear translocation.
• LicoD treatment significantly ameliorated inflammatory phenotypes in mouse models, including colitis and colitis-associated cancer.

Conclusions:

• Licochalcone D is a promising therapeutic agent for STING-driven inflammatory diseases.
• The AI-driven TransformerCPI model effectively identifies allosteric inhibitors beyond traditional binding sites.
• This study highlights a novel therapeutic approach and discovery platform for STING-related pathologies.