Glycogen Synthase Kinase 3β emerges as a master coordinator of axonal architecture by regulating microtubule organization through interactions with Shot and Tau proteins. The enzyme's kinase activity directly modulates how these cytoskeletal proteins maintain the structural integrity of nerve cell projections, revealing a previously uncharacterized pathway linking metabolic signaling to neuronal scaffolding. This mechanism represents a significant advance in understanding how GSK-3β dysfunction contributes to neurodegeneration. The enzyme has long been recognized as a therapeutic target in Alzheimer's disease due to its role in tau hyperphosphorylation, but this research illuminates its broader structural functions in healthy neurons. The Shot-Tau axis appears to be a critical vulnerability point where metabolic stress, aging, or genetic variants affecting GSK-3β activity could destabilize axonal transport and synaptic function. For brain health optimization, this suggests that interventions targeting GSK-3β regulation—whether through lithium, certain plant compounds, or lifestyle factors affecting insulin sensitivity—may preserve neuronal architecture beyond their known effects on tau pathology. However, the complex dual role of GSK-3β in both pathology and normal cellular maintenance underscores the need for precise therapeutic modulation rather than broad inhibition.