GSK3B is a constitutively active serine/threonine kinase that functions as a central negative regulator of multiple signaling pathways, particularly glucose homeostasis, Wnt signaling, and transcriptional control [UniProt]. In skeletal muscle, GSK3B phosphorylates and inactivates glycogen synthase (GYS1/GYS2), thereby suppressing glycogen synthesis and contributing to insulin regulation [UniProt]. GSK3B promotes CTNNB1/β-catenin degradation by forming a destruction complex with APC and AXIN1, phosphorylating β-catenin's N-terminus to trigger ubiquitin-proteasomal degradation [UniProt, 13]. This mechanism is particularly relevant in colorectal cancer, where elevated GSK3B activity phosphorylates and degrades TRAF6, an inhibitor of autophagy-dependent β-catenin degradation, thereby promoting epithelial-mesenchymal transition and metastasis 2. GSK3B regulates circadian rhythms by phosphorylating clock components BMAL1, CLOCK, and PER2, targeting them for proteasomal degradation [UniProt, 31]. In neurological contexts, GSK3B phosphorylates tau protein (MAPT), reducing its microtubule-stabilizing capacity and contributing to neurofibrillary pathology [UniProt]. Genetic variants in GSK3B associate with schizophrenia and major depressive disorder in Han Chinese populations, with functional polymorphisms affecting gene expression and cognitive function 45. Importantly, dual DYRK1A/GSK3B inhibition stimulates human pancreatic β-cell proliferation, offering therapeutic potential for diabetes treatment 6.