This study investigates the protective role and mechanisms of the N6-methyladenosine (m6A) RNA methyltransferase METTL3 against cerebral injury resulting from insufficient cerebral blood flow. The researchers used mouse MCAO models and HT-22 cell OGD/R models to simulate ischemic stroke-induced brain injury and neuronal damage. They found that overexpressing METTL3 inhibits the iron carrier protein TFRC by upregulating the E3 ubiquitin ligase NEDD4L, thereby alleviating oxidative damage and ferroptosis to protect the brain from ischemic injury. Mechanistically, METTL3 can methylate and stabilize NEDD4L mRNA, enhancing its expression. NEDD4L then ubiquitinates and degrades TFRC, reducing iron accumulation and neuronal ferroptosis. The study concludes that the METTL3-NEDD4L-TFRC axis is critical for inhibiting post-ischemic brain injury, and enhancing this pathway may serve as an effective strategy for stroke therapy. This research lays the theoretical foundation for developing m6A-related therapies against ischemic brain damage.This study investigates the protective role and mechanisms of the N6-methyladenosine (m6A) RNA methyltransferase METTL3 against cerebral injury resulting from insufficient cerebral blood flow. The researchers used mouse MCAO models and HT-22 cell OGD/R models to simulate ischemic stroke-induced brain injury and neuronal damage. They found that overexpressing METTL3 inhibits the iron carrier protein TFRC by upregulating the E3 ubiquitin ligase NEDD4L, thereby alleviating oxidative damage and ferroptosis to protect the brain from ischemic injury. Mechanistically, METTL3 can methylate and stabilize NEDD4L mRNA, enhancing its expression. NEDD4L then ubiquitinates and degrades TFRC, reducing iron accumulation and neuronal ferroptosis. The study concludes that the METTL3-NEDD4L-TFRC axis is critical for inhibiting post-ischemic brain injury, and enhancing this pathway may serve as an effective strategy for stroke therapy. This research lays the theoretical foundation for developing m6A-related therapies against ischemic brain damage.