Journal of ethnopharmacology · 2026
Hydroxycinnamic acids target COPII cargo sorting machinery to attenuate inflammation via the cGAS-STING axis.
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Ma Xiaojing, Wang Jiaming, Guo Yakun, Nan Yanan, Guo Linyue, Wang Yajing, Jiang Miao, Yang Mingrui, Ma Wenfu
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Hydroxycinnamic acids (HCAs), specifically cinnamic, caffeic, and ferulic acids, are core bioactive components of traditional Chinese medicinal herbs such as Cinnamomi Cortex (Cinnamomum aromaticum Nees) and Asafoetida (Ferula assa-foetida L.), used for regulating metabolic disorders and inflammation. Despite their widespread clinical application, their specific molecular targets remain unidentified.
AIM OF THE STUDY: This study elucidates HCA molecular targets and mechanisms. Using in vitro and in vivo models, we establish a mechanistic foundation for HCA-rich TCM herbs in treating T2DM and metabolic/autoinflammatory disorders.
MATERIALS AND METHODS: Crystal complex structures of HCA-COPII were solved to define binding modalities. In vitro, HCA effects on steatosis, TBK1/IRF3/STING signaling, and STING translocation were evaluated in AML12 and HEK-293T cells. In vivo, T2DM was induced in C57BL/6J mice using HFD and STZ. HCAs (30, 60 mg/kg, i.g.) were assessed against metformin for their ability to improve glucose tolerance (OGTT), insulin sensitivity (ITT/HOMA-IR), and dyslipidemia, while modulating hepatic cGAS-STING-mediated inflammation.
RESULTS: Structural and biochemical analyses show HCAs bind the Sec24 B-site of COPII competitively with STING. In vitro, HCAs reduce lipid accumulation in AML12 cells and inhibit TBK1/IRF3/STING signaling by blocking STING ER-to-Golgi translocation. In vivo, oral HCAs (30, 60 mg/kg, i.g.) restore glucose and lipid homeostasis while alleviating hepatic injury in T2DM mice. By inhibiting the cGAS-STING axis, HCAs demonstrate efficacy comparable to metformin, providing a mechanistic basis for treating metabolic and autoinflammatory diseases.
CONCLUSIONS: HCAs attenuate inflammation and steatosis in T2DM by targeting the Sec24 B-site to attenuate COPII-mediated STING trafficking, providing a novel molecular basis for their pharmacological efficacy.
AIM OF THE STUDY: This study elucidates HCA molecular targets and mechanisms. Using in vitro and in vivo models, we establish a mechanistic foundation for HCA-rich TCM herbs in treating T2DM and metabolic/autoinflammatory disorders.
MATERIALS AND METHODS: Crystal complex structures of HCA-COPII were solved to define binding modalities. In vitro, HCA effects on steatosis, TBK1/IRF3/STING signaling, and STING translocation were evaluated in AML12 and HEK-293T cells. In vivo, T2DM was induced in C57BL/6J mice using HFD and STZ. HCAs (30, 60 mg/kg, i.g.) were assessed against metformin for their ability to improve glucose tolerance (OGTT), insulin sensitivity (ITT/HOMA-IR), and dyslipidemia, while modulating hepatic cGAS-STING-mediated inflammation.
RESULTS: Structural and biochemical analyses show HCAs bind the Sec24 B-site of COPII competitively with STING. In vitro, HCAs reduce lipid accumulation in AML12 cells and inhibit TBK1/IRF3/STING signaling by blocking STING ER-to-Golgi translocation. In vivo, oral HCAs (30, 60 mg/kg, i.g.) restore glucose and lipid homeostasis while alleviating hepatic injury in T2DM mice. By inhibiting the cGAS-STING axis, HCAs demonstrate efficacy comparable to metformin, providing a mechanistic basis for treating metabolic and autoinflammatory diseases.
CONCLUSIONS: HCAs attenuate inflammation and steatosis in T2DM by targeting the Sec24 B-site to attenuate COPII-mediated STING trafficking, providing a novel molecular basis for their pharmacological efficacy.