SIX3 is a homeodomain transcription factor that acts as both a repressor and activator, binding ATTA core recognition sequences to regulate diverse developmental processes. During forebrain development, SIX3 represses WNT1 expression to ensure proper anterior-posterior diencephalic patterning and directly activates SHH in the rostral diencephalon, establishing a regulatory feedback loop critical for telencephalon formation 1. In eye development, SIX3 activates PAX6 during lens induction and suppresses WNT8B and WNT1 to promote neuroretina specification, with its actions dependent on TLE4/5 co-repressors 2. SIX3 also regulates neural progenitor proliferation and ependymal cell maturation through CCND1/CCND2 activation 3. Pathologically, SIX3 mutations cause holoprosencephaly type 2, a severe forebrain and midface malformation characterized by incomplete hemispheric separation 4. Recent evidence associates SIX3 with type 2 diabetes risk in East Asian populations 5, and reveals context-dependent roles in cancer—functioning as a tumor suppressor in most malignancies through Wnt pathway inhibition, while promoting progression in esophageal and gastric cancers 6. Additionally, SIX3 coordinates with SIX2 to regulate functional maturation of human pancreatic β cells, with reduced SIX2 levels observed in diabetic patients 3.