Activating Wnt/β-catenin signaling pathway for disease therapy: Challenges and opportunities

Wnt/β-catenin signaling pathway is essential for embryo development and adult tissue homeostasis and regeneration, abnormal regulation of the pathway is tightly associated with many disease types, suggesting that Wnt/β-catenin signaling pathway is an attractive target for disease therapy. While the Wnt inhibitors have been extensively reviewed, small molecules activating Wnt/β-catenin signaling were rarely addressed. In this article, we firstly reviewed the diseases that were associated with disruption of Wnt/β-catenin signaling pathway, including hair loss, pigmentary disorders, wound healing, bone diseases, neurodegenerative diseases and chronic obstructive pulmonary diseases, etc. We also comprehensively summarized small molecules that activated Wnt/β-catenin signaling pathway in various models in vitro and in vivo. To evaluate the therapeutic potential of Wnt activation, we focused on the discovery strategies, phenotypic characterization, and target identification of the Wnt activators. Finally, we proposed the challenges and opportunities in development of Wnt activators for pharmacological agents in term of targeting safety and selectivity.