{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSIK3 plays multifaceted roles in cancer biology and cell cycle regulation. In acute myeloid leukemia, SIK3 operates downstream of the tumor suppressor LKB1 to maintain the activity of the oncogenic transcription factor MEF2C through phosphorylation of HDAC4, while SIK3 and its family members control the nucleocytoplasmic trafficking of class IIa HDACs to regulate MEF2‐dependent transcription. In lung adenocarcinoma, loss of SIK function mirrors LKB1 inactivation, underscoring a critical tumor‐suppressive axis. By contrast, in ovarian cancer, overexpression of SIK3 promotes cell proliferation by modulating key cell cycle regulators, and in breast cancer, aberrant upregulation of SIK3—induced, for example, by high salt and interleukin‐17—accelerates cell cycle progression, enhances pro-inflammatory arginine metabolism, and facilitates metastatic traits. Furthermore, depletion of SIK3 delays mitotic exit and renders cells more sensitive to antimitotic agents, while SIK inhibition can also modulate transforming growth factor–β (TGFβ)–mediated transcriptional responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSIK3 is also integral to metabolic and inflammatory regulation. Genome‐wide analyses in populations have identified SIK3 as an Amerindian lipid gene, with risk variants associating with dyslipidemia and obesity, including elevated postprandial triglyceride levels. In adipocytes, SIK3 is dynamically regulated by cyclic AMP signaling; elevations in cAMP lead to protein kinase A–dependent phosphorylation of SIK3, promoting 14-3-3 binding and consequent reduction in its catalytic activity—mechanisms that may modulate lipolysis and other metabolic processes. In parallel, inhibition of SIKs in myeloid cells shifts cytokine production toward an anti-inflammatory profile by altering the phosphorylation of substrates such as HDAC4 and CREB-regulated transcription coactivators."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the musculoskeletal and reproductive systems, SIK3 is equally critical. In articular cartilage, conditional knockout of Sik3 in chondrocytes leads to cartilage thickening and resistance to osteoarthritis, with pharmacological inhibition (e.g., by pterosin B) reproducing these protective effects. Conversely, in ovarian granulosa cells, SIK3 is indispensable for follicle-stimulating hormone–mediated differentiation and female fertility, as knockout of SIK3 in these cells results in infertility and abnormal folliculogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSIK3 further contributes to sensory and neural functions. Genetic studies have linked SIK3 variants to hearing ability; expression analyses in the murine cochlea highlight its developmental and maintenance roles, with additional associations noted in noise-induced hearing loss. Moreover, in the context of neurodegeneration, decreased SIK3 expression in Alzheimer’s disease correlates with impaired synaptic plasticity and cognitive decline, attributable in part to dysregulation of HDAC4-mediated transcription that affects synaptic gene expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, innovative high-throughput techniques such as the NanoBRET target engagement assay have been applied to SIK3, enabling the discrimination of compound binding to SIK3 versus other isoforms and paving the way for the development of isoform-specific inhibitors with improved safety profiles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "S Charoenfuprasert, Y-Y Yang, Y-C Lee, et al. 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