GLIS3 (GLIS family zinc finger 3) is a critical transcription factor that functions as both an activator and repressor of gene expression, playing essential roles in pancreatic β-cell development, thyroid hormone biosynthesis, and metabolic regulation 1. GLIS3 directly regulates transcription by binding to consensus DNA sequences and coordinating with other transcription factors like HNF1B and NRF1 2. In pancreatic development, GLIS3 is predominantly expressed in β-cells and cooperates with PDX1, MAFA, and NEUROD1 to control insulin gene transcription and β-cell survival 3. The protein also regulates mitochondrial biogenesis and oxidative phosphorylation by directly controlling genes involved in energy metabolism, including Tfam, Ppargc1a, and various OXPHOS components 2. In thyroid development, GLIS3 becomes detectable at E15.5 and regulates thyroid hormone biosynthesis genes like Slc5a5, with its activity enhanced by TSH/PKA signaling 4. Loss-of-function mutations in GLIS3 cause a severe neonatal diabetes syndrome characterized by diabetes, congenital hypothyroidism, and polycystic kidney disease 35. Additionally, GWAS studies have identified GLIS3 variants associated with both type 1 and type 2 diabetes risk, highlighting its broad importance in glucose homeostasis 63.