2. Academic Validation
  3. Myeloid-derived MANF ameliorates ethanol-induced liver injury by enhancing microRNA-223 expression

Myeloid-derived MANF ameliorates ethanol-induced liver injury by enhancing microRNA-223 expression

  • J Gastroenterol. 2025 Mar 20. doi: 10.1007/s00535-025-02240-0.
Huiyuan Xie # 1,  Pingping Zhang # 2,  Shanru Yang 3,  Jia Du 2,  Yan Ren 3,  Xianxian Gao 3,  Na Li 3,  Tao Yang 4,  Yang Ma 5,  Xin Hou 6
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, China.
  • 2 Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China.
  • 3 Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, China.
  • 4 Department of General Surgery, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
  • 5 Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China. mayang_ahmu@126.com.
  • 6 Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, China. houxin@nbu.edu.cn.
  • # Contributed equally.
PMID: 40111540 DOI: 10.1007/s00535-025-02240-0
Abstract

Background: Myeloid cells play a pivotal role in the pathogenesis of alcoholic liver disease (ALD), yet the mechanisms regulating their function and specific contributions to ALD remain inadequately understood. This study aims to investigate the role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in the development of ALD.

Methods: Myeloid-specific Manf knockout mice and wild-type controls were fed an ethanol-based diet for 10 days, followed by a single ethanol binge. Hepatic MANF levels, along with the correlation between MANF and inflammatory factors in patients with alcoholic hepatitis, were analyzed using the GSE28619 dataset.

Results: Our study demonstrated that myeloid MANF expression in the liver was upregulated following chronic-plus-binge ethanol exposure. Deletion of the Manf gene in myeloid cells, including neutrophils, exacerbated ethanol-induced liver injury, steatosis, neutrophil infiltration, and Reactive Oxygen Species production. Mechanistic analysis revealed that MANF promotes neutrophil miR-223 expression, a key anti-inflammatory factor in these cells. MANF enhances miR-223 transcription by increasing the expression of the transcription factor PU.1 via p38 mitogen-activated protein kinase signaling. In addition, hepatic MANF levels were elevated in patients with alcoholic hepatitis and correlated with IL-6, IL-1β, and phagocytic oxidase (phox) p47phoxlevels.

Conclusion: Myeloid-derived MANF mitigates alcohol-induced liver injury by upregulating the neutrophilic p38-PU.1-miR-223 axis.

Keywords

Alcohol-associated liver disease; MANF; MicroRNA-223; Neutrophils; P38 MAPK.

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