The ischemic penumbra is critical in acute ischemic stroke (AIS) treatment, yet the regulation of precise RNA modification pathways remains unclear. Using a mouse model of ischemic stroke and human postmortem brain samples, we demonstrate that N⁶-methyladenosine (m⁶A) levels are elevated in neurons within the ischemic penumbra. Notably, m⁶A modifications by m⁶A reader protein IGF2BP1 were enriched on penumbra related circular RNA derived from oxoglutarate dehydrogenase (CircOGDH). IGF2BP1 stabilizes CircOGDH by recruiting it to stress granules, maintaining high expression in the ischemic penumbra. Knockdown of IGF2BP1 reduced CircOGDH stability and decreased neuronal apoptosis under hypoxic conditions, suggesting a protective role. Igf2bp1 knockdown also preserved synaptic integrity in MCAO mice, with increased expression of synaptic markers and improved synaptic morphology. Importantly, Igf2bp1 knockdown significantly reduced penumbra volume compared to CircOGDH inhibition alone. These findings highlight IGF2BP1 as a promising therapeutic target for modulating penumbra-related RNA expression and promoting recovery in AIS.

N⁶-Methyladenosine  /  Acute ischemic stroke  /  Ischemic penumbra  /  m⁶A reader  /  IGF2BP1  /  CircRNA  /  Stress granules  /  Therapeutic target