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<p>Epitranscriptomics modifications play an important role in sex-dependent biological phenomena. <i>N6</i>-adenosine methylation (m6A), the most prevalent epitranscriptomics modification in eukaryotic mRNA, participates in regulating various sex-specific physiological processes. Here, we generated <i>METTL4</i> knockout mice lacking methyltransferase-like 4, which mediates m6A. Behavioral analyses revealed that only female <i>METTL4</i><sup><i>−/−</i></sup> mice exhibited pain hypersensitivity, with subsequent experiments showing the involvement of METTL4-mediated m6A in this sex-differentiated biological phenotype. Further exploration demonstrated that this sex-specific pain hypersensitivity is closely associated with sex-dependent expression of uncoupling protein 2 (UCP2) in synapses. Specifically, elevated UCP2 expression in <i>METTL4</i><sup><i>−/−</i></sup> female mice enhances the efficiency of synaptic transmission by modulating mitochondrial energy metabolism at synapses. Collectively, this study identifies a distinct pathway mediated by METTL4-driven m6A modification, providing critical insights into the molecular basis of sex-specific differences in pain transmission. These findings also highlight the potential of targeting <i>METTL4</i> for sex-differentiated pain management strategies in clinical settings.</p>

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METTL4 regulates synaptic UCP2 N6-adenosine methylation to mediate pain hypersensitivity in female mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月27日

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  • Yanqiong Wu,
  • Yifan Luo,
  • Qin Xiao,
  • Xueqin Xu,
  • Wenjiao Jin,
  • Longhui Li,
  • Cheng Liu,
  • Zhigang He,
  • Zhixiao Li,
  • Juan Li,
  • Xuesong Yang,
  • Fan Jiang,
  • Zeyong Yang,
  • Daqing Ma,
  • Changbin Ke,
  • Hongbing Xiang

摘要

Epitranscriptomics modifications play an important role in sex-dependent biological phenomena. N6-adenosine methylation (m6A), the most prevalent epitranscriptomics modification in eukaryotic mRNA, participates in regulating various sex-specific physiological processes. Here, we generated METTL4 knockout mice lacking methyltransferase-like 4, which mediates m6A. Behavioral analyses revealed that only female METTL4−/− mice exhibited pain hypersensitivity, with subsequent experiments showing the involvement of METTL4-mediated m6A in this sex-differentiated biological phenotype. Further exploration demonstrated that this sex-specific pain hypersensitivity is closely associated with sex-dependent expression of uncoupling protein 2 (UCP2) in synapses. Specifically, elevated UCP2 expression in METTL4−/− female mice enhances the efficiency of synaptic transmission by modulating mitochondrial energy metabolism at synapses. Collectively, this study identifies a distinct pathway mediated by METTL4-driven m6A modification, providing critical insights into the molecular basis of sex-specific differences in pain transmission. These findings also highlight the potential of targeting METTL4 for sex-differentiated pain management strategies in clinical settings.