METTL3 regulates TFRC ubiquitination and ferroptosis through stabilizing NEDD4L mRNA to impact stroke. This study investigates the protective role of METTL3, an N6-methyladenosine (m6A) RNA methyltransferase, against cerebral injury caused by insufficient cerebral blood flow. METTL3 stabilizes NEDD4L mRNA, enhancing its expression. NEDD4L, an E3 ubiquitin ligase, ubiquitinates and degrades TFRC, reducing iron accumulation and neuronal ferroptosis. Ferroptosis, a form of regulated cell death, is exacerbated by iron overload in ischemic stroke. METTL3 overexpression inhibits ferroptosis by upregulating NEDD4L, which in turn reduces TFRC levels and iron accumulation. This study reveals that the METTL3-NEDD4L-TFRC axis is critical for inhibiting postischemic brain injury. Enhancing this pathway may serve as an effective strategy for stroke therapy. The findings suggest that targeting the METTL3-NEDD4L-TFRC axis could be a promising approach to mitigate iron-mediated oxidative damage and ferroptosis in stroke. The study provides a theoretical foundation for developing m6A-related therapies against ischemic brain damage.METTL3 regulates TFRC ubiquitination and ferroptosis through stabilizing NEDD4L mRNA to impact stroke. This study investigates the protective role of METTL3, an N6-methyladenosine (m6A) RNA methyltransferase, against cerebral injury caused by insufficient cerebral blood flow. METTL3 stabilizes NEDD4L mRNA, enhancing its expression. NEDD4L, an E3 ubiquitin ligase, ubiquitinates and degrades TFRC, reducing iron accumulation and neuronal ferroptosis. Ferroptosis, a form of regulated cell death, is exacerbated by iron overload in ischemic stroke. METTL3 overexpression inhibits ferroptosis by upregulating NEDD4L, which in turn reduces TFRC levels and iron accumulation. This study reveals that the METTL3-NEDD4L-TFRC axis is critical for inhibiting postischemic brain injury. Enhancing this pathway may serve as an effective strategy for stroke therapy. The findings suggest that targeting the METTL3-NEDD4L-TFRC axis could be a promising approach to mitigate iron-mediated oxidative damage and ferroptosis in stroke. The study provides a theoretical foundation for developing m6A-related therapies against ischemic brain damage.