Salt-inducible kinase 3 (SIK3) (SIK3)

Salt-inducible kinase 3 (SIK3) is a serine/threonine kinase belonging to the AMPK-related kinase family that serves as a master regulator of metabolism, immune response, and circadian rhythms [1, 12]. It functions by phosphorylating downstream substrates, most notably cAMP-regulated transcriptional coactivators (CRTCs) and class IIa histone deacetylases (HDACs), which leads to their cytoplasmic sequestration and the subsequent modulation of gene expression programs [2, 13]. In the immune system, SIK3 acts as a rheostat for cytokine production; its inhibition promotes an anti-inflammatory state by increasing IL-10 levels and decreasing pro-inflammatory cytokines like TNF-alpha [9, 10]. SIK3 is also a critical regulator of sleep homeostasis and the circadian clock, where it influences the stability of the PER2 protein [12, 17]. In oncology, SIK3 is frequently overexpressed and contributes to tumor growth and chemoresistance in cancers such as ovarian and breast cancer [3, 16]. Therapeutic targeting of SIK3, often through dual SIK2/3 or pan-SIK inhibitors, is being explored for the treatment of autoimmune diseases, osteoporosis, and various malignancies [5, 15].

Other names

QSKSalt-inducible protein kinase 3Serine/threonine-protein kinase SIK3L19HGNC:29165

Inhibition of SIK3 kinase activity, which prevents the phosphorylation of cAMP-regulated transcriptional coactivators (CRTCs) and class IIa histone deacetylases (HDACs) [2, 13]. This leads to their nuclear translocation and the subsequent modulation of gene expression programs involved in inflammation (e.g., increasing IL-10, decreasing TNF-alpha), gluconeogenesis, and bone formation [9, 10, 12].