Journal of animal science and biotechnology · 2026
METTL3 inhibition attenuates AFB1-induced hepatic fibrosis by suppressing m6A-mediated hepatic stellate cell activation.
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Zhao Yulan, Feng Yue, Yuan Wenbo, Zhang Tingyu, Zhao Ruqian
Аннотация
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.
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.