The ZNRF1 signaling pathway mediates oxidative stress–induced neuronal apoptosis and axonal degeneration. Oxidative stress induced by treatment with 6OHDA or H₂O₂ or generated by NADPH oxidases in axons upon traumatic injury activates EGFR tyrosine kinase activity and leads to ZNRF1 phosphorylation at Y103. This stimulates the E3 ubiquitin ligase activity of ZNRF1, which ubiquitinates and targets AKT for degradation via the UPS. Degradation of AKT relieves the inhibitory phosphorylation of GSK3β, which then phosphorylates CRMP2 and subjects it to degradation. In axons, CRMP2 is required for microtubule stabilization, whose disassembly results in axonal degeneration. In soma, oxidative stress activates this same ZNRF1 signaling pathway, which causes cleavage and activation of caspase 3, leading to neuronal apoptosis.