Eukaryotic elongation factor 2 kinase (eEF2K): Mechanisms and pharmacological significance in metabolic diseases.

Eukaryotic elongation factor 2 kinase (eEF2K) is an atypical Ca2+/calmodulin-dependent serine/threonine kinase that inhibits the elongation phase of protein synthesis by phosphorylating its sole known substrate, eukaryotic elongation factor 2 (eEF2). As protein synthesis is one of the most energy-intensive cellular processes, eEF2K functions as an energy-conservation mechanism under nutrient or energy stress, thereby maintaining cellular homeostasis. It has emerged as a central hub linking energy metabolism, cellular stress responses, and disease progression. In metabolic diseases, aberrant eEF2K activity contributes to pathological processes. In type 2 diabetes (T2D) and its complications, eEF2K modulates insulin signaling, mitochondrial function, and stress responses, whereas in atherosclerosis, it affects endothelial function, inflammation, and autophagy, promoting disease progression. Consequently, eEF2K is considered a promising therapeutic target. Despite increasing interest, systematic studies on eEF2K in metabolic regulation remain limited, and its precise roles in metabolic reprogramming, immune-inflammatory modulation, and stress adaptation are not fully elucidated. Pharmacological strategies-including direct inhibitors, indirect modulators, targeted protein degraders (TPD), and paradoxical activators-are under exploration, offering novel avenues for treatment. This review summarizes the structure and regulatory network of eEF2K, highlights its roles in energy metabolism, oxidative stress, autophagy, and inflammation, and discusses its pathophysiological significance and therapeutic potential in T2D, atherosclerosis (AS), and Alzheimer's disease (AD), providing insights for future research and drug development. In addition, eEF2K is regarded as a "central hub linking metabolic inflammation, protein translation, and autophagy," highlighting its potential as a target for TPD therapies. This perspective provides broader disease coverage, deeper mechanistic insights, and new directions for drug development in metabolic and neurodegenerative disorders.