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

ABSTRACT

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.