The N-terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism  

作　　者：Xue Wang Chunyou Ning Xingyi Cheng Zhengzhong Wu Dongbo Wu Xuemei Ding Cunxiang Ju Zhihang Zhou Lingfeng Wan Wei Zhao Peiliang Shi 

机构地区：[1]GemPharmatech Chengdu Co.,Ltd.,Chengdu,China [2]Center of Infectious Diseases,West China Hospital,Sichuan University,Chengdu,China [3]Gempharmatech Shanghai Co.,Ltd.,Shanghai,China [4]Department of Gastroenterology,the Second Affiliated Hospital of Chongqing Medical University,Chongqing,China [5]Fatty Liver Disease Center of Integrated Chinese and Western Medicine,Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing,China [6]School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College,Chengdu,China [7]Department of Clinical Biochemistry,School of Laboratory Medicine,Chengdu Medical College,Chengdu,China [8]GemPharmatech Co.,Ltd.,Guangdong,China

出　　处：《Animal Models and Experimental Medicine》2025年第1期114-125,共12页动物模型与实验医学(英文)

基　　金：National Natural Science Foundation of China,Grant/Award Number:82174292;Key Project of Jiangsu Provincial Administration of Traditional Chinese Medicine,Grant/Award Number:ZD202312;Natural Science Foundation of Laboratory Medicine School in Chengdu Medical College,Grant/Award Number:JYZK202203;Sichuan Province Science and Technology Program,Grant/Award Number:2024NSFSC0577 and 2021YFG0316;Technology innovation group project of Foshan 2019,Grant/Award Number:FS0AA-KJ919-4402-0027。

摘　　要：Background:The emerging incidence of pathogenic liver conditions is turning into a major concern for global health.Induction of pyroptosis in hepatocytes instigates cel-lular disintegration,which in turn liberates substantial quantities of pro-inflammatory intracellular substances,thereby accelerating the advancement of liver fibrosis.Consequently,directing therapeutic efforts towards inhibiting pyroptosis could po-tentially serve as an innovative approach in managing inflammation related chronic hepatic disorders.Methods:GSDMD-NT^(ki/wt)mice and Alb-cre^(ki/wt)mice were generated using CRISPR/Cas9 technology.After crossing the two strains together,we induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis.We analyzed differ-entially expressed genes by RNA sequencing and explored their biological functions.The efficacy of obeticholic acid(OCA)in the treatment of liver fibrosis was assessed.Results:Doxycycline-treated GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice showed severe liver damage,vacuolation of hepatocytes,increased collagen fibers,and accumulation of lipid droplets.The expression of liver fibrosis related genes was greatly increased in the doxycycline-treated mouse liver compared with untreated mouse liver.RNA-sequencing showed that upregulated differentially expressed genes were involved in inflammatory responses,cell activation,and metabolic processes.Treatment with OCA alleviated the liver fibrosis,with reduced ALT and AST levels seen in the GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice.Conclusions:We successfully constructed a novel mouse model for liver fibrosis.This GSDMD-NT-induced fibrosis may be mediated by abnormal lipid metabolism.Our re-sults demonstrated that we successfully constructed a mouse model of liver fibrosis,and GSDMD-NT induced fibrosis by mediating lipid metabolism.

关 键 词：GSDMD-NT lipid metabolism liver fibrosis NASH PYROPTOSIS 

分 类 号：R575.2[医药卫生—消化系统]