Biochimica et biophysica acta. Molecular basis of disease · 2026
The m6A reader IGF2BP2 promotes hepatic fibrosis by stabilizing AEBP1 mRNA and regulating GRB2-mediated hepatic stellate cell activation.
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Hu Youwen, Xiao Yangyang
Аннотация
BACKGROUND: The occurrence of hepatic fibrosis (HF) is closely related to the activation of hepatic stellate cells (HSCs), but the epitranscriptional regulatory mechanisms involved have not been fully elucidated. This study aims to explore the role and molecular mechanisms of the m6A reader protein IGF2BP2 in HSC activation and HF.
METHODS: This study used a CCl4-induced mouse HF model and a TGF-β1-stimulated LX-2 cell model. The interactions between IGF2BP2, AEBP1, and GRB2 were analyzed using bioinformatics, RIP-qPCR, MeRIP-qPCR, RNA pull-down, ChIP-qPCR, dual-luciferase reporter assays, and gene knockdown/overexpression techniques. The effects of this signaling axis on HSC activation, proliferation, migration, and fibrosis markers were assessed by Western blot, qPCR, IHC/IF, EdU, and Transwell assays.
RESULTS: The study found that AEBP1 was significantly upregulated in HF samples, mouse models, and activated LX-2 cells, with increased m6A modification of its mRNA. IGF2BP2, an upstream regulator, enhances AEBP1 stability and protein expression by binding to the m6A sites within AEBP1 mRNA. AEBP1 activates GRB2 expression as a transcription factor. Functional rescue experiments showed that overexpressing AEBP1 or GRB2 reversed the inhibitory effects of IGF2BP2 or AEBP1 knockdown on fibrosis. In vivo, IGF2BP2 knockdown alleviated HF and inhibited the AEBP1-GRB2 axis.
CONCLUSION: This study reveals a novel mechanism by which IGF2BP2 regulates HF through the m6A-AEBP1-GRB2 axis, providing new potential targets for the diagnosis and treatment of HF.
METHODS: This study used a CCl4-induced mouse HF model and a TGF-β1-stimulated LX-2 cell model. The interactions between IGF2BP2, AEBP1, and GRB2 were analyzed using bioinformatics, RIP-qPCR, MeRIP-qPCR, RNA pull-down, ChIP-qPCR, dual-luciferase reporter assays, and gene knockdown/overexpression techniques. The effects of this signaling axis on HSC activation, proliferation, migration, and fibrosis markers were assessed by Western blot, qPCR, IHC/IF, EdU, and Transwell assays.
RESULTS: The study found that AEBP1 was significantly upregulated in HF samples, mouse models, and activated LX-2 cells, with increased m6A modification of its mRNA. IGF2BP2, an upstream regulator, enhances AEBP1 stability and protein expression by binding to the m6A sites within AEBP1 mRNA. AEBP1 activates GRB2 expression as a transcription factor. Functional rescue experiments showed that overexpressing AEBP1 or GRB2 reversed the inhibitory effects of IGF2BP2 or AEBP1 knockdown on fibrosis. In vivo, IGF2BP2 knockdown alleviated HF and inhibited the AEBP1-GRB2 axis.
CONCLUSION: This study reveals a novel mechanism by which IGF2BP2 regulates HF through the m6A-AEBP1-GRB2 axis, providing new potential targets for the diagnosis and treatment of HF.