GRHL2 is a transcription factor that functions as a critical regulator of epithelial development and neural tube closure during embryogenesis 1. It binds to the consensus sequence 5'-AACCGGTT-3' to activate or repress distinct target genes, playing cooperative roles with GRHL3 in establishing neural closure zones 1. In epithelial tissues, GRHL2 regulates tight junction assembly by upregulating claudin genes (CLDN3/4) and controls epithelial morphogenesis through transcriptional activation of apical junctional complex components, including CDH1 [UniProt]. GRHL2 exhibits functional redundancy with GRHL3 in epidermal wound repair and coordinates lung epithelial differentiation through regulatory loops with NKX2-1. In cancer biology, GRHL2 displays context-dependent functions: it acts as an EMT suppressor by resisting mesenchymal reprogramming in breast cancer metastasis 2, while its activity is modulated by SUMOylation at lysine 159, which enhances transcriptional activity 3. GRHL2 is also implicated in prostate aging through regulation of the CDK19-p53-p21 axis, with gene therapy restoring epithelial homeostasis 4. Disease-associated mutations include truncating variants causing autosomal dominant hearing loss 5, and GRHL2 polymorphisms influence noise-induced hearing loss susceptibility 6. Additionally, GRHL2 interacts with MLL3 in squamous cancers to regulate immune response pathways and checkpoint blockade efficacy 7.