Molecular mechanisms and clinical implications of Wnt pathway inhibition.

The dysregulation of the evolutionarily conserved Wnt signaling pathway is a fundamental factor in the pathogenesis of numerous diseases. This review consolidates current knowledge regarding the therapeutic targeting of Wnt signaling inhibitors. Endogenous inhibitors exert multi-layered regulatory control by mechanisms such as extracellular ligand sequestration, receptor antagonism, cytoplasmic β-catenin degradation, and nuclear transcriptional repression, thereby ensuring precise regulation of the pathway. Dysfunction in these regulatory mechanisms often results in aberrant Wnt activation and disease development. Consequently, there is a substantial focus on the development of pharmacological Wnt inhibitors, including small molecules, biologic agents, and natural products that modulate Wnt activity. Although these agents offer significant therapeutic potential, challenges remain due to the critical physiological roles of the Wnt pathway, which may lead to potential on-target toxicity and resistance. This review underscores the pivotal roles and therapeutic targeting of Wnt inhibitors, highlighting the molecular rationale behind inhibition and the ongoing efforts to translate this understanding into effective clinical strategies for cancer and other diseases.