Hydroxycinnamic acids target COPII cargo sorting machinery to attenuate inflammation via the cGAS-STING axis

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Hydroxycinnamic acids (HCAs) from traditional Chinese medicines regulate metabolic disorders and inflammation.
• Specific molecular targets of HCAs remain largely unidentified despite clinical use.

Purpose of the Study:

• Elucidate HCA molecular targets and mechanisms of action.
• Establish a mechanistic basis for HCA-rich herbs in treating type 2 diabetes (T2DM) and related disorders.

Main Methods:

• Determined crystal complex structures of HCA-COPII to define binding.
• Assessed HCA effects on steatosis and TBK1/IRF3/STING signaling in vitro.
• Evaluated HCA efficacy against metformin in a mouse model of T2DM, assessing glucose/lipid homeostasis and hepatic inflammation.

Main Results:

• HCAs bind the COPII Sec24 B-site, competitively inhibiting STING.
• HCAs reduced lipid accumulation and inhibited STING signaling by blocking ER-to-Golgi translocation in vitro.
• In vivo, HCAs improved glucose/lipid homeostasis and reduced hepatic inflammation in T2DM mice, comparable to metformin.

Conclusions:

• HCAs attenuate inflammation and steatosis in T2DM by targeting COPII-mediated STING trafficking.
• This study provides a novel molecular mechanism for the pharmacological efficacy of HCAs.
• Identified HCAs as potential therapeutic agents for metabolic and autoinflammatory diseases.