SIK3 (salt-inducible kinase 3) is a serine/threonine kinase of the AMPK family with established roles in sleep regulation, immune function, and skeletal development. Mechanistically, SIK3 functions as a positive regulator of mTOR signaling by promoting DEPTOR degradation 1 and negatively regulates cAMP signaling through CRTC2/TORC2 phosphorylation 2. SIK3 operates within the LKB1-SIK3-HDAC4 signaling cascade, where it phosphorylates HDAC4 to regulate sleep-wake cycles; gain-of-function SIK3 in excitatory neurons increases sleep quantity and EEG delta power 3, while SIK3 loss-of-function decreases sleep 4. A naturally occurring SIK3-N783Y mutation associated with human natural short sleep trait reduces kinase activity and alters phosphoproteomic signatures at synaptic sites 4. Beyond sleep, SIK3 contributes to tumor suppression in non-small cell lung cancer through LKB1-mediated activation 2, supports chondrocyte differentiation during skeletogenesis 1, maintains auditory function 5, and modulates immune responses via cytokine regulation 6. Clinically, SIK3 dysfunction associates with spondyloepimetaphyseal dysplasia (Krakow type) and clonal hematopoiesis with elevated infection and malignancy risk 7. SIK3 inhibition represents a therapeutic strategy for inflammatory diseases 6.