Mena-dependent local translation of PI3K-p85 coordinates the axonal regenerative program upon injury

Local translation (LT) is one of the first processes activated after nerve injury and is critically coupled with the intrinsic ability of axons to grow and regenerate. However, regulation of LT in adult axons remains highly unexplored. Here we identify the actin regulator Mena, as a key mediator of adult axon regeneration, via its control of local protein synthesis. We show that Mena directly associates with PI3K-p85 mRNA and regulates its LT in injured sciatic nerve axons, thereby activating the downstream AKT/mTOR pathway. Genetic ablation of Mena disrupts this intrinsic response, resulting in impaired axonal LT and diminished axon regeneration in vivo . Our findings identify a Mena-dependent mechanism that remodels the local axonal proteome and reveal a critical link between mRNA regulation and metabolic signaling during axon regeneration.