AXIN2 (axin 2) is a critical negative regulator of the Wnt/β-catenin signaling pathway that functions as a scaffold protein in the β-catenin destruction complex 1. AXIN2 facilitates the phosphorylation and degradation of β-catenin by interacting with GSK3β, thereby preventing aberrant Wnt pathway activation 23. The protein undergoes post-translational regulation through GSK3β-mediated phosphorylation, which promotes its ubiquitination by β-Trcp2 and subsequent proteasomal degradation 2. AXIN2 is paradoxically both a target and regulator of Wnt signaling, as its expression is induced by β-catenin activation while simultaneously functioning to suppress the pathway 1. Loss-of-function mutations in AXIN2 are associated with colorectal cancer development and isolated tooth agenesis, with the mandibular and maxillary second premolars being most frequently affected 45. In colorectal cancer, AXIN2 can be targeted by epigenetic regulators like ALKBH5, leading to mRNA instability and pathway hyperactivation 6. Clinically, AXIN2 variants serve as potential biomarkers for cancer predisposition in patients with tooth agenesis, and therapeutic targeting of AXIN2 shows promise for cancer treatment 25.