High-throughput screening of small molecule Wnt/β-catenin activators for hair and nail growth

Hair and nails, though structurally different, both rely on Wnt/β-catenin signaling for regeneration. To identify small molecules that enhance this pathway, we screened 5,170 FDA-approved and natural compounds using HEK293 cells with a TCF/LEF luciferase reporter. Nine compounds significantly activated Wnt signaling, including antivirals (imidocarb, proflavine, aminoacridine), anticancer agents (entinostat, enzastaurin, abemaciclib), and GSK-3β inhibitors (BIO, CP21R7). Aminoacridine and proflavine markedly upregulated RSPO3 and RSPO4 while suppressing WIF1. In mice, aminoacridine—especially combined with minoxidil—showed the strongest hair regrowth, while proflavine and imidocarb enhanced nail elongation. These results reveal new therapeutic candidates for hair and nail regeneration. High-throughput screening identifies FDA approved and natural compounds that activate Wnt/β-Catenin signaling, promoting hair and nail regrowth through cell-based and animal models, with potential for repurposing in regenerative therapy.