Nuclear β-catenin: molecular regulation, challenges and therapeutic opportunities

The spatiotemporal control of Wnt signaling orchestrates embryonic development and tissue homeostasis, while dysregulation of this pathway has been linked to a variety of diseases, including cancer, fibrosis and neurodegeneration. Although nuclear accumulation of β-catenin serves as a hallmark of Wnt pathway hyperactivation, the mechanisms controlling nuclear β-catenin remain obscure and are subjected to some conflicting hypotheses. In this narrative review, we summarize current understanding of the complex interplays fine-tunning the nucleocytoplasmic trafficking and subcellular distribution of β-catenin. We also present computational analysis to explore candidate molecules regulating nuclear β-catenin and suggest new perspectives to future study. Finally, we discuss how these insights could pave the way for mechanism-based approaches to target "undruggable" Wnt signaling for Wnt-driven diseases.