Hic-5缺陷通过CXCL1-CXCR2轴抑制中性粒细胞迁移，从而减轻MAFLD。

Hic-5 deficiency attenuates MAFLD by inhibiting neutrophils migration via the CXCL1-CXCR2 axis.

作者信息

Ren Bingyu, Li Han, Liu Shenglu, Huang Zhiwei, Bai Junjie, Jiang Zhonghao, Xu Tongjie, Gu Boyuan, Yu Wenhao, Sun Lei, Tan Peng, Fu Wenguang

机构信息

Department of General Surgery (Hepatopancreatobiliary Surgery), Department of Biliary-Pancreatic Center, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou City, 646000, Sichuan Province, China.

Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.

出版信息

J Gastroenterol. 2025 Sep 9. doi: 10.1007/s00535-025-02293-1.

DOI:10.1007/s00535-025-02293-1

PMID:40924147

Abstract

BACKGROUND AND AIMS

Inflammatory cell infiltration in the liver is a hallmark of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the pathological events that trigger the infiltration of inflammatory cells to mediate MAFLD pathogenesis remains poorly understood. This study aims to investigate the function and mechanism of Hic-5 on hepatic inflammation of MAFLD.

METHODS

MAFLD animal models were fed a methionine- and choline-deficient (MCD) diet in Hic-5 knockout mice. Liver tissues were analyzed by immunohistochemical staining, immunofluorescence and flow cytometry, with a particular focus on the impact on the immune microenvironment.

RESULTS

Hic-5 deficiency alleviates the severity of MAFLD, particularly the inflammation response. Gain- and loss-of-function experiments revealed that Hic-5 deficiency results in decreased neutrophil proliferation and increased apoptosis, as well as impaired migration. Conversely, Hic-5 overexpression had the opposite effects. This study confirmed that METTL3-mediated methylation of mA stabilizes Hic-5 mRNA and promotes its expression, which in turn regulates the infiltration of neutrophils by the CXCL1-CXCR2 axis.

CONCLUSIONS

The study reveals the role of Hic-5 in regulating neutrophils and indicates that it may be a potential therapeutic target for MAFLD.

摘要

背景与目的

肝脏中的炎症细胞浸润是代谢功能障碍相关脂肪性肝病（MAFLD）的一个标志。然而，引发炎症细胞浸润以介导MAFLD发病机制的病理事件仍知之甚少。本研究旨在探讨Hic-5在MAFLD肝脏炎症中的作用及机制。

方法

在Hic-5基因敲除小鼠中给予蛋氨酸和胆碱缺乏（MCD）饮食以建立MAFLD动物模型。通过免疫组织化学染色、免疫荧光和流式细胞术分析肝脏组织，特别关注对免疫微环境的影响。

结果

Hic-5缺乏减轻了MAFLD的严重程度，尤其是炎症反应。功能获得和功能丧失实验表明，Hic-5缺乏导致中性粒细胞增殖减少、凋亡增加以及迁移受损。相反，Hic-5过表达则产生相反的效果。本研究证实，METTL3介导的mA甲基化稳定了Hic-5 mRNA并促进其表达，进而通过CXCL1-CXCR2轴调节中性粒细胞的浸润。