CAMKK2 is a calcium/calmodulin-dependent protein kinase that functions as a critical hub in calcium-triggered signaling cascades. Its primary substrates include CAMK1, CAMK4, and AMPK, which it phosphorylates in response to Ca2+ signals 1. CAMKK2 operates through two major downstream pathways: the CAMKK2-AMPK axis and the CAMKK2-CAMKI-CREB pathway 2. Through AMPK activation, CAMKK2 regulates autophagy, mitochondrial function, and metabolic homeostasis 34. CAMKK2-mediated AMPK phosphorylation (at T172) is essential for autophagy-lysosomal pathway activation and mitochondrial quality control 4. Dysregulation of CAMKK2 signaling contributes to multiple diseases: in nonalcoholic steatohepatitis, AMPK activation via CAMKK2 alleviates hepatic pathology 3; in Alzheimer's disease, GLP-1R agonists enhance CAMKK2-AMPK signaling to reduce amyloid-beta generation 1; in cancer (intrahepatic cholangiocarcinoma and castration-resistant prostate cancer), CAMKK2 promotes proliferation through both AMPK-dependent and CREB-dependent mechanisms 52; and in ovarian cancer, calcium chelation inactivates CAMKK2 to trigger ferroptosis 6. CAMKK2 emerges as a therapeutic target with diverse clinical applications across metabolic, neurodegenerative, and malignant diseases.