SIK1 (salt-inducible kinase 1) is a serine/threonine protein kinase of the AMP-activated protein kinase family 1 that functions as a critical regulator of multiple cellular pathways with both tumor-suppressive and context-dependent roles in cancer. SIK1 is catalytically activated through phosphorylation by the upstream kinase LKB1 1 and mediates tumor-suppressive effects in non-small cell lung cancer through phosphorylation of CRTC2, suppressing AP1 and IL6 signaling 2. In hepatic glucose metabolism, SIK1 negatively regulates gluconeogenesis by phosphorylating CRTC2 and promoting its cytoplasm-to-nucleus translocation, leading to suppression of gluconeogenic enzymes G6Pase and PEPCK 3. Conversely, in pancreatic cancer, SIK1 promotes ferroptosis resistance by phosphorylating HDAC5 at Ser498, stabilizing it through 14-3-3 protein interaction, which deacetylates STAT6 and upregulates the iron transporter SLC7A11 4. In breast cancer with hyperactive AKT signaling, AKT-mediated phosphorylation of SIK1 compromises its tumor-suppressive functions by relieving SIK1-mediated repression of STAT3, promoting tumorigenesis 5. SIK1 expression is significantly downregulated in osteoarthritis synovium and serves as a diagnostic biomarker for OA progression 6. These findings establish SIK1 as a therapeutic target with context-dependent roles in metabolic and oncogenic signaling pathways.