IRF6 is a sequence-specific DNA-binding transcription factor that functions as a critical regulator of epithelial differentiation and development. As a member of the interferon regulatory factor family 1, IRF6 plays a key role in the keratinocyte proliferation-differentiation switch essential for epidermal development. Recent mechanistic studies reveal that glucose directly binds IRF6, enabling its dimerization, DNA binding, and transcriptional activation of pro-differentiation genes including GRHL1, GRHL3, HOPX, and PRDM1 2. Beyond skin, IRF6 regulates mammary epithelial cell differentiation and is autonomously required for osteoblast differentiation and bone mineralization in craniofacial tissues 3. IRF6 mutations cause non-syndromic orofacial clefts (NSOC), the most common craniofacial malformation, making it the best-documented NSOC susceptibility gene 4. Genetic studies identified a Finnish-enriched variant (rs570516915) that impairs IRF6 autoregulation through altered transcription factor binding in an upstream enhancer, specifically increasing cleft palate risk 5. Additionally, IRF6 mutations are frequently detected in head and neck squamous cell carcinoma, where dysregulation of genes controlling squamous differentiation—including IRF6—drives carcinogenesis 6. Emerging evidence suggests IRF6 involvement in Alzheimer's disease pathology, where its expression is modulated by APOE-ε4 status 7.