GLI2 is a transcriptional regulator of the Hedgehog signaling pathway that functions as both an activator and repressor of gene expression through sequence-specific DNA binding. Acting downstream of Smoothened signaling, GLI2 is phosphorylated by the ciliary kinase DYRK2 at conserved serine residues, which promotes its dissociation from the suppressor protein SUFU and nuclear translocation 1. GLI2 plays critical roles in developmental processes including skeletal morphogenesis, limb development, and pituitary formation 12. Pathogenic GLI2 variants cause Culler-Jones syndrome, a rare autosomal dominant disorder characterized by hypopituitarism (present in 91% of patients), pituitary stalk interruption, and extrapituitary manifestations including polydactyly (27%), neurocognitive disorders (38%), and cardiac/renal abnormalities 23. GLI2 variants represent the most frequent genetic cause of syndromic congenital hypopituitarism (68% of cases), though disease expression shows significant phenotypic heterogeneity even within families 23. In cancer, aberrant GLI2 activation promotes tumorigenesis through multiple mechanisms. GLI2 cooperates with oncogenic KRAS to upregulate growth-promoting genes including Ccnd1, N-Myc, and Bcl2 in pancreatic cancer 4. GLI2 drives chemoresistance in gastric cancer via GLI2/DEC1/ZEB1-mediated epithelial-mesenchymal transition 5, and facilitates immunotherapy resistance by upregulating WNT and prostaglandin signaling to create an immunosuppressive tumor microenvironment 6. TGF-β1/SMAD3-driven GLI2 activation in hepatocellular carcinoma promotes stemness, metastasis, and chemo-resistance, with high GLI2 expression correlating with poor disease-free survival 7.