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<p>The rapid escalation of oxidative and nitrosative stress during ischemia/reperfusion (I/R) triggers neuronal damage, leading to severe neurological deficits and long-term disability. N6-methyladenosine (m<sup>6</sup>A), a highly abundant RNA modification in the brain, undergoes dynamic changes following acute I/R injury, and regulates stroke pathogenesis and neurological outcomes. However, the molecular mechanisms by which m<sup>6</sup>A influences acute I/R injury responses remain elusive. Our study reveals that the expression of key I/R pathogenesis pathways positively correlates with the expression of m<sup>6</sup>A reader proteins. Modulating expression of YTHDF1, a neuron-enriched reader protein of m<sup>6</sup>A, results in bidirectional changes in oxidative stress response&#xa0;and neuronal viability under I/R conditions. We have identified <i>p53</i> mRNA as a critical target of m<sup>6</sup>A methylation and YTHDF1, driving the translation of p53 protein in a context- and m<sup>6</sup>A-dependent manner, which exacerbates oxidative stress and ferroptosis. This novel mechanism suggests the potential of targeting the m<sup>6</sup>A reader protein as a strategic avenue for developing neuroprotective therapies to mitigate I/R injury.</p> Graphical abstract <p>m<sup>6</sup>A-dependent YTHDF1 binding to <i>p53</i> mRNA promotes its translation and ferroptosis during acute cerebral ischemia/reperfusion (I/R)</p> <p>Critical points:</p> <p>• I/R upregulates YTHDF1 expression and its binding to m<sup>6</sup>A-modfied <i>p53</i> mRNA;</p> <p>• Binding by YTHDF1 promotes translation of <i>p53</i> mRNA and induces ferroptosis;</p> <p>• AAV-mediated knockdown of YTHDF1 alleviates I/R-induced neuronal damage in acute phase.</p> <p></p>

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YTHDF1 promotes p53 translation and induces ferroptosis during acute cerebral ischemia/reperfusion through m6A-dependent binding

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Xinyu Chang,
  • Bingwu Li,
  • Wanxu Huang,
  • Aixia Chen,
  • Shengmin Zhu,
  • Yueyang Liu,
  • Xiaoling Liu,
  • Jingyu Yang,
  • Dan Ohtan Wang

摘要

The rapid escalation of oxidative and nitrosative stress during ischemia/reperfusion (I/R) triggers neuronal damage, leading to severe neurological deficits and long-term disability. N6-methyladenosine (m6A), a highly abundant RNA modification in the brain, undergoes dynamic changes following acute I/R injury, and regulates stroke pathogenesis and neurological outcomes. However, the molecular mechanisms by which m6A influences acute I/R injury responses remain elusive. Our study reveals that the expression of key I/R pathogenesis pathways positively correlates with the expression of m6A reader proteins. Modulating expression of YTHDF1, a neuron-enriched reader protein of m6A, results in bidirectional changes in oxidative stress response and neuronal viability under I/R conditions. We have identified p53 mRNA as a critical target of m6A methylation and YTHDF1, driving the translation of p53 protein in a context- and m6A-dependent manner, which exacerbates oxidative stress and ferroptosis. This novel mechanism suggests the potential of targeting the m6A reader protein as a strategic avenue for developing neuroprotective therapies to mitigate I/R injury.

Graphical abstract

m6A-dependent YTHDF1 binding to p53 mRNA promotes its translation and ferroptosis during acute cerebral ischemia/reperfusion (I/R)

Critical points:

• I/R upregulates YTHDF1 expression and its binding to m6A-modfied p53 mRNA;

• Binding by YTHDF1 promotes translation of p53 mRNA and induces ferroptosis;

• AAV-mediated knockdown of YTHDF1 alleviates I/R-induced neuronal damage in acute phase.