GSK-3β

Glycogen synthase kinase-3β (GSK-3β) is a constitutively active serine/threonine kinase that regulates numerous cellular substrates and functions as a central signaling node in metabolism, development, and cell fate control^[1]. Mechanistically, GSK-3β participates in multiple signaling pathways, including Wnt/β-catenin, PI3K/Akt, Notch, and NF-κB networks, where its phosphorylation-dependent activity influences transcriptional regulation, cellular differentiation, and stress responses^[2][3]. Through these pathway interactions, GSK-3β contributes to the control of glucose metabolism and broader cardiometabolic homeostasis, while dysregulated GSK-3β signaling has been linked to pathological remodeling and disease progression in diverse experimental models^[4][1]. In neurological disease models, GSK-3β has been associated with hyperphosphorylated tau pathology and neuronal dysfunction, supporting its relevance as a target for mechanistic studies of neurodegeneration^[3]. Compared with the closely related isoform GSK-3α, GSK-3β exhibits both overlapping and isoform-specific biological functions, and genome-wide as well as genetic studies demonstrate distinct downstream targets and physiological roles for the two kinases^[4][5][6]. This isoform divergence is particularly important for experimental design because GSK-3α and GSK-3β can exert different or even opposing effects in specific biological contexts^[4]. For experimental applications, small-molecule GSK-3 inhibitors remain widely used research tools; however, many available compounds lack isoform selectivity, emphasizing the need for isoform-specific pharmacological and genetic approaches when investigating GSK-3β-dependent mechanisms^[6][5].