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Updated: May 29, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
METTL3 inhibition attenuates AFB1-induced hepatic fibrosis by suppressing m6A-mediated hepatic stellate cell
Yulan Zhao1,2, Yue Feng1,2,3, Wenbo Yuan1,2
1MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, People's Republic of China.
Background:
Aflatoxin B1 (AFB1) is a potent hepatotoxic mycotoxin and a major environmental risk factor for hepatocellular carcinoma (HCC). Hepatic fibrosis is a critical intermediate stage in this process, and METTL3-mediated m6A modification may represent an important post-transcriptional mechanism linking AFB1-induced liver injury to fibrogenic progression.
Methods:
AFB1-induced hepatic fibrosis was evaluated using in vivo mouse models and in vitro cultured hepatic stellate cells (HSC). Global m6A methylation and methyltransferase-like 3 (METTL3) expression were assessed by liquid chromatography-mass spectrometry, Western blotting, single-nucleus RNA sequencing, and quantitative real-time PCR. METTL3 was inhibited using small interfering RNA or the selective inhibitor STM2457. Molecular docking was performed to identify potential METTL3-binding compounds, followed by functional validation.
Results:
AFB1 exposure promoted hepatic fibrosis and HSC activation, accompanied by global m6A hypermethylation and upregulation of METTL3. METTL3 increased the m6A modification of collagen-related transcripts, enhancing their stability and promoting extracellular matrix production in a YTHDF1-dependent manner. Inhibition of METTL3 suppressed HSC activation and fibrotic gene expression both in vitro and in vivo. Molecular docking identified saxagliptin as a potential METTL3-binding compound, which reduced AFB1-induced HSC activation and extracellular matrix accumulation, consistent with the effects of STM2457.
Conclusions:
These findings indicate that METTL3 functions as a post-transcriptional regulator in AFB1-induced liver fibrosis via m6A modification. METTL3 inhibition, achieved via genetic knockdown or selective inhibitors, affects HSC activation and fibrotic gene expression, supporting its role as a therapeutic target in AFB1-induced liver fibrosis.
Insights
Aflatoxin B1 exposure causes liver fibrosis by upregulating METTL3, which modifies collagen transcripts. Inhibiting METTL3 reduces fibrosis, suggesting it as a therapeutic target for aflatoxin-induced liver injury.
Area of Science:
- Hepatology and Molecular Biology
- Epigenetics and RNA Modification
Background:
- Aflatoxin B1 (AFB1) is a mycotoxin linked to liver cancer, with hepatic fibrosis as a key intermediate.
- METTL3-mediated m6A modification is implicated in linking AFB1 liver injury to fibrosis progression.
Purpose of the Study:
- To investigate the role of METTL3 in AFB1-induced liver fibrosis.
- To explore METTL3 as a potential therapeutic target for AFB1-induced liver fibrosis.
Main Methods:
- AFB1-induced hepatic fibrosis models (in vivo and in vitro HSC).
- Assessed global m6A methylation and METTL3 expression using LC-MS, Western blot, snRNA-seq, and qRT-PCR.
- Inhibited METTL3 using siRNA or STM2457; identified potential inhibitors via molecular docking.
Main Results:
- AFB1 exposure promoted fibrosis and HSC activation, with increased m6A and METTL3.
- METTL3 enhanced collagen transcript stability and ECM production via YTHDF1.
- METTL3 inhibition suppressed HSC activation and fibrotic gene expression in vitro and in vivo.
- Saxagliptin identified as a METTL3 inhibitor, reducing AFB1-induced HSC activation and ECM accumulation.
Conclusions:
- METTL3 acts as a post-transcriptional regulator in AFB1-induced liver fibrosis through m6A modification.
- METTL3 inhibition (genetic or pharmacologic) impacts HSC activation and fibrotic gene expression.
- METTL3 is a promising therapeutic target for AFB1-induced liver fibrosis.
