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

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 (mA), 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 mA 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 mA reader proteins. Modulating expression of YTHDF1, a neuron-enriched reader protein of mA, 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 mA methylation and YTHDF1, driving the translation of p53 protein in a context- and mA-dependent manner, which exacerbates oxidative stress and ferroptosis. This novel mechanism suggests the potential of targeting the mA reader protein as a strategic avenue for developing neuroprotective therapies to mitigate I/R injury.