SIK3, or salt-inducible kinase 3, is a key component in multiple intracellular signaling pathways. It is downstream of LKB1 kinase in a pathway that also involves histone deacetylases HDAC4 and HDAC5. SIK3 has been implicated in regulating various biological processes, including sleep-wake cycles, neuronal excitability, and cellular energy metabolism [3,6]. Genetic mouse models have been crucial in studying SIK3's functions.

In NSCLC, conditional genetic loss of Sik1, along with Sik3, enhanced tumor growth in Kras-dependent lung cancer mouse models, indicating SIK3's role in tumor-suppression as a target of LKB1 [1]. In mice, Sik3 deficiency in GABA-ergic or NMS-producing neurons in the suprachiasmatic nucleus delayed arousal peak and lengthened the circadian cycle, while its gain-of-function mutant allele in GABAergic neurons had the opposite effects [2]. In excitatory neurons, loss of SIK3 decreased sleep, suggesting its role in regulating sleep quantity and depth [3]. In 5×FAD AD transgenic mouse models, conditional deletion of SIK3 in dorsal hippocampal neurons accelerated cognitive deterioration and impaired synaptic plasticity [4]. Osteoclast-specific SIK3 conditional knockout mice showed increased bone mass and an osteopetrosis phenotype, highlighting SIK3's role in bone resorption [5]. In Drosophila, loss of SIK3 led to neuronal hyperexcitability and seizures due to impaired glial K⁺ and water homeostasis [7].

In summary, SIK3 is essential in regulating sleep-wake rhythms, synaptic plasticity, tumor-suppression, bone resorption, and glial-mediated neuronal excitability. Gene-knockout and conditional-knockout mouse models have been instrumental in revealing SIK3's functions in diseases such as NSCLC, Alzheimer's disease, and osteoporosis, providing insights into potential therapeutic targets for these conditions.