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Background <p>N6-methyladenosine (m<sup>6</sup>A) modification is implicated in various diseases pathogenesis and physiological processes. We investigated the regulatory function of METTL3, a central m<sup>6</sup>A methyltransferase, in mediating m<sup>6</sup>A modification of YY1. This study aims to delineate how m<sup>6</sup>A modification of YY1 governs the pathogenesis of radiation-induced lung fibroblast injury and to elucidate its underlying molecular mechanism.</p> Methods <p>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 m<sup>6</sup>A-dependent mechanisms and further assessed the involvement of IGF2BP1 in modulating YY1 mRNA stability.</p> Results <p>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 m<sup>6</sup>A modification. METTL3 depletion attenuated RILI progression, whereas YY1 overexpression partially ameliorated this phenotype. Crucially, IGF2BP1 directly interacts with m<sup>6</sup>A-modified YY1 mRNA to influence their expression and stability.</p> Conclusion <p>Our data show that METTL3-mediated m<sup>6</sup>A modification of YY1 plays a crucial role in RILI pathogenesis, and IGF2BP1 serves as an essential mediator for the stability of YY1 mRNA.</p>

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A novel mechanism of radiation-induced lung injury: METTL3 mediates fibrogenesis through N6-methyladenosine modification of YY1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月4日

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  • Weiqiang Xu,
  • Junxuan Yi,
  • Xinfeng Wei,
  • Mingwei Wang,
  • Mingqi Zhao,
  • Mengdie Zhao,
  • Xinyan Wang,
  • Yannan Shen,
  • Zhicheng Wang,
  • Shunzi Jin

摘要

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.