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Hepatic IκBζpromotes alcohol-associated liver disease and acute hepatitis by enhancing CXCL1-Mediated neutrophil infiltration

文献类型：期刊论文

作者Liu, Li5,6; Qian, Shengying4,6; Li, Wenjun5; Dong, Siyue5; Ya, Ru4,6; He, Yanghuan3; Huang, Haohua2; Chen, Yingfen4,6; Ma, Ningning4,6; Hao, Yawen4,6
刊名FREE RADICAL BIOLOGY AND MEDICINE
出版日期2025-09-01
卷号237页码:558-569
关键词Nfkbiz ALD Acute liver injury GalNac
ISSN号0891-5849
DOI10.1016/j.freeradbiomed.2025.06.022
英文摘要Background & aims: Neutrophil infiltration is a critical driver of liver injury; however, the factors regulating neutrophil recruitment remain incompletely understood. I kappa B zeta, encoded by Nfkbiz, is a key transcriptional factor known to influence the inflammatory response. This study aims to investigate whether I kappa B zeta contributes to liver injury and how it affects neutrophil infiltration. Methods: Liver-specific Nfkbiz knockout mice (Nfkbiz triangle Hep) and control mice (Nfkbizf/f) were generated and subjected to various liver disease models. RNA sequencing and chromatin immunoprecipitation (ChIP) assays were used to identify molecular targets of I kappa B zeta. Results: We found that Nfkbiz mRNA levels were significantly elevated in the livers of patients with severe alcohol-associated hepatitis and in mouse models of alcohol-associated liver disease (ALD). This elevation correlated with alanine aminotransferase (ALT) levels. Notably, hepatocyte-specific Nfkbiz deficiency reduced neutrophil infiltration and mitigated liver injury and inflammation following Gao-binge alcohol feeding. Transcriptomic and ChIP assays identified chemokine (C-X-C motif) ligand 1 (Cxcl1) as a direct downstream target of I kappa B zeta. Furthermore, Nfkbiz triangle Hep mice were also more resistant to concanavalin A (ConA)-induced hepatitis but not acetaminophen or carbon tetrachloride-induced acute liver injury, showing decreased neutrophil infiltration and reduced CXCL1 expression. Finally, therapeutic inhibition of I kappa B zeta using GalNac-siNfkbiz injection alleviated ALDrelated liver injury and inflammation, suggesting its potential as a novel therapeutic approach for ALD and other liver diseases characterized by neutrophilic inflammation.
WOS关键词INJURY
资助项目National Key Research and Development Program of China[2023YFA1800804] ; National Science and Technology Innovation 2030 Major Program, China[2024ZD0530604] ; National Natural Science Foundation of China, China[82270601] ; National Natural Science Foundation of China, China[82270596]
WOS研究方向Biochemistry & Molecular Biology ; Endocrinology & Metabolism
语种英语
WOS记录号WOS:001513942200002
出版者ELSEVIER SCIENCE INC
源URL[http://119.78.100.183/handle/2S10ELR8/318630]  
专题新药研究国家重点实验室
通讯作者Wang, Xiaolin; He, Yong
作者单位1.Indiana Univ Sch Med, Dept Med, Div Gastroenterol & Hepatol, Indianapolis, IN USA
2.Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Infect Dis, Sch Med, Shanghai, Peoples R China
3.Fudan Univ, Huadong Hosp, Dept Gastroenterol, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
6.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med SIMM, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Li,Qian, Shengying,Li, Wenjun,et al. Hepatic IκBζpromotes alcohol-associated liver disease and acute hepatitis by enhancing CXCL1-Mediated neutrophil infiltration[J]. FREE RADICAL BIOLOGY AND MEDICINE,2025,237:558-569.
APA Liu, Li.,Qian, Shengying.,Li, Wenjun.,Dong, Siyue.,Ya, Ru.,...&He, Yong.(2025).Hepatic IκBζpromotes alcohol-associated liver disease and acute hepatitis by enhancing CXCL1-Mediated neutrophil infiltration.FREE RADICAL BIOLOGY AND MEDICINE,237,558-569.
MLA Liu, Li,et al."Hepatic IκBζpromotes alcohol-associated liver disease and acute hepatitis by enhancing CXCL1-Mediated neutrophil infiltration".FREE RADICAL BIOLOGY AND MEDICINE 237(2025):558-569.

入库方式： OAI收割

来源：上海药物研究所

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