Medical School of Chinese PLA, Beijing, China.
Department of Gastroenterology, The Second Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
Mol Med. 2024 Sep 27;30(1):160. doi: 10.1186/s10020-024-00924-6.
The cGAS-STING pathway is an important component of the innate immune system and plays significant role in acetaminophen-induced liver injury (AILI). Pentagalloylglucose (PGG) is a natural polyphenolic compound with various beneficial effects, including anti-cancer, antioxidant, anti-inflammatory, and liver-protective properties; however, whether it can be used for the treatment of AILI and the specific mechanism remain unclear.
A cell culture model was created to study the effect of PGG on cGAS-STING pathway activation using various techniques including western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence (IF), and immunoprecipitation (IP). The effect of PGG was investigated in vivo by establishing a dimethylxanthenone acetic acid (DMXAA)-mediated activation model. An AILI model was used to evaluate the hepatoprotective and therapeutic effects of PGG by detecting liver function indicators, liver histopathology, and cGAS-STING pathway-related indicators in mice with AILI.
PGG blocked cGAS-STING pathway activation in bone marrow-derived macrophages (BMDMs), THP-1 cells, and peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, PGG inhibited the generation of type I interferons (IFN-I) and the secretion of inflammatory factors in DMXAA-induced in vivo experiments. In addition, PGG also reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), improved liver tissue damage and apoptosis, and inhibited the cGAS-STING pathway activation caused by acetaminophen. In terms of the mechanism, PGG disrupted the connection between STING and TBK1.
PGG exerts a protective effect against AILI by blocking the cGAS-STING pathway, offering a promising treatment strategy.
cGAS-STING 通路是先天免疫系统的重要组成部分，在对乙酰氨基酚诱导的肝损伤（AILI）中发挥重要作用。五没食子酰葡萄糖（PGG）是一种天然多酚化合物，具有多种有益作用，包括抗癌、抗氧化、抗炎和保肝作用；然而，它是否可用于治疗 AILI 以及具体机制尚不清楚。
使用包括 Western blot（WB）、实时定量聚合酶链反应（RT-qPCR）、免疫荧光（IF）和免疫沉淀（IP）在内的各种技术，建立细胞培养模型研究 PGG 对 cGAS-STING 通路激活的影响。通过建立二甲氧萘乙酸（DMXAA）介导的激活模型，在体内研究 PGG 的作用。通过检测 AILI 小鼠的肝功能指标、肝组织病理学和 cGAS-STING 通路相关指标，评估 PGG 在 AILI 中的保肝和治疗作用。
PGG 阻断了体外骨髓来源的巨噬细胞（BMDMs）、THP-1 细胞和外周血单核细胞（PBMCs）中的 cGAS-STING 通路激活。此外，PGG 还抑制了 DMXAA 诱导的体内实验中 I 型干扰素（IFN-I）的产生和炎症因子的分泌。此外，PGG 还降低了血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）和碱性磷酸酶（ALP）水平，改善了肝组织损伤和细胞凋亡，并抑制了对乙酰氨基酚引起的 cGAS-STING 通路激活。在机制方面，PGG 破坏了 STING 和 TBK1 之间的连接。
PGG 通过阻断 cGAS-STING 通路对 AILI 发挥保护作用，为治疗 AILI 提供了一种有前途的治疗策略。
