Small Molecule-Induced Neuronal Differentiation: A Promising Path Toward Cell-Based Regenerative Therapies.

One of the main bottlenecks in regenerative therapy is low neuronal differentiation after stem cell transplantation. Several approaches can induce neuronal differentiation, such as transcription factor manipulation, growth factors and cytokines, optogenetics, metabolic reprogramming, and Small Molecules (SMs). Each method has advantages and disadvantages; however, shortening the induction time and the maximum rate of neuronal differentiation is a high priority when selecting a method. Among all approaches, SMs can match these properties. Furthermore, SMs can target the developmental signaling pathways in neuronal maturation and generation. For example, they modulate WNT, Notch, TGF-β/SMAD, Sonic Hedgehog (Shh), FGF, Retinoic Acid, MAPK/ERK, PI3K/AKT/mTOR, cAMP/PKA, BMP, JAK/STAT, and Nrf2 pathways. These pathways are essential for regulating neuronal differentiation, and SMs serve as a powerful tool for manipulating them in both research and therapeutic contexts. Therefore, we examine recent studies on SMs and discuss the pitfalls and challenges encountered during neuronal differentiation in preclinical research. Additionally, we review relevant studies that have advanced to clinical stages. Ultimately, based on our findings, we conclude that SMs hold significant promise for inducing neurons from stem cells; however, comprehensive clinical studies are necessary to demonstrate their efficacy in stem cell therapy for neurological disorders.