Enhancing m6A modification in the motor cortex facilitates corticospinal tract remodeling after spinal cord injury

Abstract Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N 6 -methyladenosine (m 6 A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m 6 A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein (METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m 6 A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m 6 A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m 6 A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.