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

Cell Biol Toxicol. 2025 Jul 1;41(1):112. doi: 10.1007/s10565-025-10061-3.

Abstract

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.

Keywords: Ferroptosis; I/R injury; Translation; YTHDF1; m6A; p53.

MeSH terms

  • Acute Disease
  • Animals
  • Brain Injuries* / genetics
  • Brain Injuries* / metabolism
  • Brain Injuries* / pathology
  • Cell Line
  • Ferroptosis*
  • Male
  • Mice
  • Nerve Tissue Proteins* / genetics
  • Nerve Tissue Proteins* / metabolism
  • Oxidative Stress
  • Protein Binding
  • Protein Biosynthesis
  • RNA Methylation*
  • RNA Splicing Factors* / genetics
  • RNA Splicing Factors* / metabolism
  • Reperfusion Injury* / genetics
  • Reperfusion Injury* / metabolism
  • Reperfusion Injury* / pathology
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • YTHDC1 protein, mouse
  • Nerve Tissue Proteins
  • RNA Splicing Factors
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53