Targeting eukaryotic elongation factor 2 (eEF2)/eEF2 kinase in neurological and neuropsychiatric Disorders: Mechanisms, therapeutic Implications, and translational challenges.

Eukaryotic elongation factor 2 kinase (eEF2K) phosphorylates eukaryotic elongation factor 2 (eEF2) and slows translation elongation. In the nervous system, this pathway links neuronal activity, calcium signaling, energy status, and stress responses to selective protein synthesis programs that shape synaptic plasticity, circuit excitability, and cell survival. Dysregulated eEF2K/eEF2 signaling has been implicated in epilepsy, Alzheimer's disease, Parkinson's disease, major depressive disorder, Down syndrome, and other brain conditions. However, the literature remains fragmented, largely preclinical, and often interpreted in an overly therapeutic manner. This review synthesizes the field using a mechanistic framework. Across disorders, altered eEF2 phosphorylation converges on five major axes: synaptic plasticity and excitatory/inhibitory balance, oxidative and mitochondrial stress responses, neuroinflammation/neuroimmune regulation, and aging-related neurogenesis and cognitive resilience. In chronic neurodegenerative and neurodevelopmental settings, excessive eEF2K activity is frequently associated with impaired de novo protein synthesis, synaptic dysfunction, and cognitive decline, whereas genetic or pharmacological suppression can improve selected behavioral and electrophysiological outcomes. By contrast, in acute metabolic stress or certain immune-cell contexts, eEF2K activity may serve adaptive and anti-inflammatory functions. These findings indicate that eEF2K has context-dependent, rather than uniformly pathogenic, roles. We also highlight major translational barriers, including dependence on rodent models, limited causal human data, incomplete cell-type resolution, and the off-target liabilities of commonly used inhibitors such as NH125 and A-484954. Overall, the eEF2K/eEF2 axis represents a biologically important but therapeutically complex target that will require selective, cell-aware, and stage-specific modulation. Future progress depends on better biomarkers, human models, and more selective brain-penetrant inhibitors.