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

IF 5.5 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Journal of Gastroenterology Pub Date : 2025-09-09 DOI:10.1007/s00535-025-02293-1

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

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引用次数: 0

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 m⁶A 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.

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Hic-5缺乏通过抑制中性粒细胞通过CXCL1-CXCR2轴的迁移来减弱MAFLD。

背景和目的：肝脏炎症细胞浸润是代谢功能障碍相关脂肪性肝病（MAFLD）的标志。然而，引发炎症细胞浸润介导MAFLD发病机制的病理事件仍然知之甚少。本研究旨在探讨Hic-5在MAFLD肝脏炎症中的作用及机制。方法：以Hic-5基因敲除小鼠为模型，饲喂蛋氨酸和胆碱缺乏（MCD）饲料。通过免疫组织化学染色、免疫荧光和流式细胞术分析肝组织，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。功能增益和功能丧失实验显示，Hic-5缺乏导致中性粒细胞增殖减少，细胞凋亡增加，以及迁移受损。相反，Hic-5过表达具有相反的效果。本研究证实mettl3介导的m6A甲基化稳定Hic-5 mRNA并促进其表达，进而调节中性粒细胞通过CXCL1-CXCR2轴的浸润。结论：本研究揭示了Hic-5在调节中性粒细胞中的作用，提示其可能是MAFLD的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Gastroenterology 医学-胃肠肝病学

CiteScore

12.20

自引率

1.60%

发文量

审稿时长

4-8 weeks

期刊介绍： The Journal of Gastroenterology, which is the official publication of the Japanese Society of Gastroenterology, publishes Original Articles (Alimentary Tract/Liver, Pancreas, and Biliary Tract), Review Articles, Letters to the Editors and other articles on all aspects of the field of gastroenterology. Significant contributions relating to basic research, theory, and practice are welcomed. These publications are designed to disseminate knowledge in this field to a worldwide audience, and accordingly, its editorial board has an international membership.