谷胱甘肽过氧化酶4通过磷脂酶Cβ2/分散状反式高尔基体网络/Nlrp3炎性小体途径介导热射病急性肝损伤的作用和机制

急性肝损伤（ALI）是热射病（HS）的常见并发症，目前HS并发ALI机制不明，治疗手段有限，是导致HS高病死率的重要原因之一。我们前期研究证实以Nlrp3炎性小体激活为标志的炎症反应在HS并发ALI进展中扮演重要角色，但Nlrp3炎性小体激活机制仍不明确。预实验结果提示HS条件下损伤肝组织中谷胱甘肽过氧化酶4（GPX4）表达下调，与Nlrp3炎性小体激活呈负相关关系，GPX4可能经PLCβ2生成的二酰甘油（DAG）调控分散状反式高尔基体网络（dTGN）形成，介导Nlrp3炎性小体激活。本研究拟通过体内外实验，确证HS条件下GPX4通过dTGN介导肝组织中Nlrp3炎性小体激活的作用，阐明GPX4经PLCβ2生成的DAG调控dTGN形成的机制，探索GPX4调节PLCβ2表达的关键分子及作用机制，以期为HS并发ALI的防治提供精准靶点，提高其治愈率。

Acute liver injury （ALI）is one of the most common complications of heatstroke （HS）, which is associated with the poor prognosis of the HS patients. The mechanism of HS-induced acute liver injury is still not clear，so there is no specific treatment method for it. Our previous study confirmed that the inflammatory response marked by NOD-like receptor family pyrin domain containing 3 inflammasome （Nlrp3 inflammasome）activation played an important role in the progression of ALI induced by HS, but the mechanism of Nlrp3 inflammasome activation remains unclear. Pre-experimental experiments suggested that the expression of glutathione peroxidase 4（GPX4）was down-regulated in the liver tissue of the HS animal and was negatively correlated with the degree of the Nlrp3 inflammasome activation. Further preliminary experiments showed the GPX4 can regulate the formation of dispersed trans-Golgi network（dTGN） through diacylglycerol（DAG）generated by Phospholipase C beta 2（PLCβ2），then mediate the Nlrp3 inflammasome activation. This study intends to determine the role of GPX4 in mediating the Nlrp3 inflammasome activation in HS state through the formation of dTGN by in vitro and in vivo experiments，clarify the mechanism of GPX4 on regulating the formation of dTGN via DAG generated by PLCβ2, explore the key molecules and detailed mechanism of GPX4 on regulating the PLCβ2 expression levels. In short, this study hopes to provide a new perspective for the prevention and treatment of HS and improve the cure rate of HS.