METTL14 downregulation drives S100A4+ monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression
Open accessAbstract
Without intervention, a considerable proportion of patients with metabolism‐associated fatty liver disease (MAFLD) will progress from simple steatosis to metabolism‐associated steatohepatitis (MASH), liver fibrosis, and even hepatocellular carcinoma. However, the molecular mechanisms that control progressive MAFLD have yet to be fully determined. Here, we unraveled that the expression of the N6-methyladenosine (m6A) methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD, whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation, liver injury, and fibrosis. Conversely, hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet (HFD). Notably, in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner, which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1 + Ccr2 + monocyte-derived macrophages (Mo-macs). In detail, Cx3cr1 + Ccr2 + Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells (HSCs) to promote liver fibrosis. Further experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1 + Ccr2 + Mo-macs. Restoration of METTL14 or GLS2, or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and fibrosis. Taken together, these findings indicate potential therapies for the treatment of MAFLD progression.
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This metabolic alteration promotes oxidative stress, which activates the MyD88/NF-κB pathway in monocytes.
“This metabolic alteration promotes oxidative stress, which in turn activates the myeloid differentiation primary response 88 (MyD88)/NF-κB pathway in monocytes.”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [56]
The Results section on GLS2 reports increased oxidative stress in hepatocytes, and the Discussion links it to DAMP release. The Results section on S100A4 says DAMPs *could* activate MyD88/NF-κB signaling in monocyte-derived macrophages, while experiments support a role for CX3CR1 in that pathway. The claim overstates that proposed link as established activation by oxidative stress in monocytes; page numbers were not available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThis signaling cascade drives the expansion of a pathogenic S100A4+ macrophage subset that secretes pro-inflammatory factors and activates HSCs, linking steatosis to inflammation and fibrosis.
“This signaling cascade drives the expansion of a pathogenic S100A4+ macrophage subset that secretes pro-inflammatory factors and activates HSCs, thereby linking steatosis to inflammation and fibrosis (56).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [56]
The Results report accumulation of S100A4-expressing monocyte-derived macrophages in Mettl14-deficient mice, while the Discussion links CX3CR1/MyD88/NF-κB signaling to S100A4 transcription, HSC activation, inflammation, and fibrosis (page numbers unavailable). The paper does not establish that this signaling cascade drives expansion of the subset, rather than S100A4 expression within it, or directly show that the subset secretes pro-inflammatory factors. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn MASLD, downregulation of the m6A methyltransferase METTL14 leads to reduced expression of glutaminase 2 (GLS2).
“In MASLD, downregulation of the m6A methyltransferase METTL14 leads to reduced expression of glutaminase 2 (GLS2).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [56]
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- Authors
- Wang, Y.-F., Zhang, W.-L., Li, Z.-X., Liu, Y., Tan, J., Yin, H.-Z., Zhang, Z.-C., Piao, X.-J., Ruan, M.-H., Dai, Z.-H., Wang, S.-J., Mu, C.-Y., Yuan, J.-H., Sun, S.-H., Liu, H., & Yang, F.
- Affiliations
- Chinese PLA General Hospital (CN)
- Second Military Medical University (CN)
- Corresponding author
- Liu, Hui
- Yang, Fu
- Venue
- Signal Transduction and Targeted Therapy
- Published
- 2024-04-17
- Volume
- 9
- Issue
- 1
- Pages
- 91-91
- ISSN
- 2059-3635 (ISSN-L)
- PMC
- PMC11021505
- OpenAlex
- W4394866892
- Cited by
- 69
- References
- 66
- Citations by year
- 2026: 37 · 2025: 25 · 2024: 7
- FWCI
- 21.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81972657, 81830085)
- National Key Research and Development Program of China
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- METTL14, N6-methyladenosine, m6A RNA methylation, GLS2, YTHDF1, S100A4, monocyte-derived macrophages, MyD88/NF-κB signaling, hepatic stellate cells, liver fibrosis, oxidative stress, high-fat diet, hepatocyte-specific knockout, M1-like macrophages
- MeSH terms
- S100 Calcium-Binding Protein A4, Animals, Humans, Liver Cirrhosis, Macrophages, Methyltransferases, Down-Regulation, NF-kappa B, Receptors, Chemokine, Mice, Myeloid Differentiation Factor 88, Non-alcoholic Fatty Liver Disease
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