CaMKK2 in Central Nervous System Disorders: Context-Dependent Signaling and Therapeutic Challenges

Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) couples calcium signaling to metabolic, inflammatory, and transcriptional pathways and has been implicated in a broad range of central nervous system (CNS) disorders. However, its effects vary across disease settings, and the mechanisms underlying this context dependence remain poorly defined. This narrative review examines genetic, transcriptomic, biochemical, cellular, and in vivo evidence on the roles of CaMKK2 across CNS disorders, with emphasis on signaling pathways, cell type-specific functions, and implications for therapeutic targeting. CaMKK2-associated pathways influence neurovascular responses, synaptic function, protein homeostasis, inflammation, and tumor progression through signaling networks involving AMPK, CaMK1, CaMK4, and Akt. CaMKK2 can exert distinct, and in some settings opposing, effects depending on cell type, downstream pathway engagement, intervention timing, and pathological context. Pharmacological studies remain limited by incomplete selectivity, insufficient characterization of CNS pharmacokinetics, and context-dependent biological effects. Moreover, much of the mechanistic evidence derives from experimental models, and validated biomarkers for clinical translation remain limited. Overall, CaMKK2 emerges as a context-dependent signaling node linking calcium signaling to metabolic and inflammatory pathways in CNS disorders, with therapeutic potential but substantial challenges for therapeutic translation.