Zeng Xin, Wu Tian, Xu Qing, Li Lan, Yuan Yujia, Zhu Min, Liu Wen, Fu Fudong, Wu Zhenru, Yao Han, Liao Guangneng, Lu Yanrong, Cheng Jingqiu, Liu Jingping, Shi Yujun, Chen Younan
Department of Liver Transplantation Center and National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China.
Liver Int. 2025 Feb;45(2):e16234. doi: 10.1111/liv.16234.
Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for cirrhosis and hepatocellular carcinoma, for which there is currently no effective treatment. This study aimed to investigate the regulatory mechanism between endoplasmic reticulum stress (ER stress) and pyroptosis in the liver under the context of MASH.
Pyroptosis was examined in both in vivo and in vitro ER stress models. The expression levels of nucleotide-binding oligomerisation domain-like receptor protein 3 (NLRP3), gasdermin D (GSDMD), caspase-1, IL-1β, and IL-18 tended to increase, and "ASC specks" colocalised with the swollen ER in living cells. However, in the pyroptotic model, increased ER stress was not observed. Moreover, the overexpression of inositol-requiring enzyme 1α (IRE-1α), one of the main ER stress sensors, led to increases in the levels of NLRP3 and GSDMD. However, after IRE-1α was blocked by chemical inhibitors or siRNAs, pyroptosis was also abrogated. These data showed that ER stress regulated pyroptosis through IRE-1α. Furthermore, the immunoprecipitation results clearly indicated that GSDMD efficiently bound to IRE-1α when ER stress was stimulated. In the MASH model, IRE-1α was specifically inhibited by pharmacological or genetic methods, which improved the pathology of MASH by alleviating ER stress and pyroptosis. In patients with MASH, both ER stress markers and pyroptosis markers including IRE-1α, glucose-regulated protein 78, GSDMD/GSDMD-N, p20, and NLRP3, are highly expressed in the liver.
This study revealed that ER stress may regulate pyroptosis through IRE-1α-GSDMD pathway, which accelerates the progression of MASH. These findings may offer new insights for the treatment of MASH.
代谢功能障碍相关脂肪性肝炎（MASH）是肝硬化和肝细胞癌的重要危险因素，目前尚无有效的治疗方法。本研究旨在探讨MASH背景下内质网应激（ER应激）与肝脏细胞焦亡之间的调控机制。
在体内和体外ER应激模型中检测细胞焦亡情况。核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）、gasdermin D（GSDMD）、半胱天冬酶-1、白细胞介素-1β和白细胞介素-18的表达水平趋于升高，且“ASC斑点”在活细胞中与肿胀的内质网共定位。然而，在细胞焦亡模型中，未观察到ER应激增加。此外，主要的ER应激传感器之一肌醇需求酶1α（IRE-1α）的过表达导致NLRP3和GSDMD水平升高。然而，在IRE-1α被化学抑制剂或小干扰RNA阻断后，细胞焦亡也被消除。这些数据表明ER应激通过IRE-1α调节细胞焦亡。此外，免疫沉淀结果清楚地表明，当ER应激被激活时，GSDMD能有效地与IRE-1α结合。在MASH模型中，通过药理学或遗传学方法特异性抑制IRE-1α，可通过减轻ER应激和细胞焦亡改善MASH的病理状况。在MASH患者中，ER应激标志物和细胞焦亡标志物，包括IRE-1α、葡萄糖调节蛋白78、GSDMD/GSDMD-N、p20和NLRP3，在肝脏中均高表达。
本研究表明ER应激可能通过IRE-1α-GSDMD途径调节细胞焦亡，从而加速MASH的进展。这些发现可能为MASH的治疗提供新的见解。
