A novel mechanism of radiation-induced lung injury: METTL3 mediates fibrogenesis through N6-methyladenosine modification of YY1
Abstract Background N6-methyladenosine (m6A) modification is implicated in various diseases pathogenesis and physiological processes. We investigated the regulatory function of METTL3, a central m6A methyltransferase, in mediating m6A modification of YY1. This study aims to delineate how m6A modific...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-06-01
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| Series: | Journal of Translational Medicine |
| Online Access: | https://doi.org/10.1186/s12967-025-06614-z |
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| Summary: | Abstract Background N6-methyladenosine (m6A) modification is implicated in various diseases pathogenesis and physiological processes. We investigated the regulatory function of METTL3, a central m6A methyltransferase, in mediating m6A modification of YY1. This study aims to delineate how m6A modification of YY1 governs the pathogenesis of radiation-induced lung fibroblast injury and to elucidate its underlying molecular mechanism. Methods The expression of METTL3 and YY1 were quantified in human lung fibroblasts and Radiation-Induced Lung Injury (RILI) mouse models. We systematically investigated whether METTL3 regulates YY1 expression through m6A-dependent mechanisms and further assessed the involvement of IGF2BP1 in modulating YY1 mRNA stability. Results METTL3 was significantly upregulated at both transcriptional and translational levels in RILI mouse lungs and irradiated human lung fibroblasts. YY1 expression was mechanistically depended on METTL3-mediated m6A modification. METTL3 depletion attenuated RILI progression, whereas YY1 overexpression partially ameliorated this phenotype. Crucially, IGF2BP1 directly interacts with m6A-modified YY1 mRNA to influence their expression and stability. Conclusion Our data show that METTL3-mediated m6A modification of YY1 plays a crucial role in RILI pathogenesis, and IGF2BP1 serves as an essential mediator for the stability of YY1 mRNA. |
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| ISSN: | 1479-5876 |