Navigating the Complexity: A Comprehensive Review of GSK-3 Inhibition in Regenerative Medicine

Glycogen synthase kinase-3 (GSK-3) is a central regulator of numerous cellular signaling pathways, with critical roles in metabolism, proliferation, differentiation, and tissue regeneration. This review explores the multifaceted effects of pharmacological GSK-3 inhibition across multiple body districts, focusing on its highly context-dependent impact. It has been proven that blocking GSK-3 promotes embryonic stem cell self-renewal, neuronal differentiation, osteogenesis, and dentinogenesis, while it has an inhibitory effect on adipogenesis. GSK-3 inhibition effects on muscle, heart, liver, and skin are more complex and often contradictory, influenced by critical factors, such as dosage, timing of administration, cellular microenvironment, and isoform specificity (GSK-3α vs. GSK-3β). A dual role also emerges in fibrosis and epithelial-mesenchymal transition processes, where GSK-3 inhibition can either have a suppressive or promoting role. Despite its promising therapeutic potential in regenerative medicine, clinical translation is still hindered by its contradictory effects in some tissues, the need for fine-tuned treatment regimens, and the lack of isoform-specific inhibitors. Selective targeting approaches and robust preclinical studies are thus essential to fully harness the therapeutic potential of GSK-3 modulation.