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

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

  • J Gastroenterol. 2025 Sep 9. doi: 10.1007/s00535-025-02293-1.
Bingyu Ren # 1,  Han Li # 1,  Shenglu Liu 1,  Zhiwei Huang 1,  Junjie Bai 1,  Zhonghao Jiang 1,  Tongjie Xu 1,  Boyuan Gu 1,  Wenhao Yu 1,  Lei Sun 1,  Peng Tan 2,  Wenguang Fu 3 4
Affiliations

Affiliations

  • 1 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.
  • 2 Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China. tanpeng@swmu.edu.cn.
  • 3 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. fuwg@swmu.edu.cn.
  • 4 Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China. fuwg@swmu.edu.cn.
  • # Contributed equally.
PMID: 40924147 DOI: 10.1007/s00535-025-02293-1
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.

Keywords

C-X-C motif chemokine ligand 1; Hepatic stellate cell; Hic-5; MAFLD; Neutrophil.

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