YTHDF1 promotes p53 translation and induces ferroptosis during acute cerebral ischemia/reperfusion through m(6)A-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 (m(6)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(6)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(6)A reader proteins. Modulating expression of YTHDF1, a neuron-enriched reader protein of m(6)A, 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 m(6)A methylation and YTHDF1, driving the translation of p53 protein in a context- and m(6)A-dependent manner, which exacerbates oxidative stress and ferroptosis. This novel mechanism suggests the potential of targeting the m(6)A reader protein as a strategic avenue for developing neuroprotective therapies to mitigate I/R injury.