NKX2-4 is a homeodomain-containing transcription factor belonging to the NK2.1 family, homologous to the Drosophila scro gene 1. As a DNA-binding transcription factor, it functions in regulating gene expression through RNA polymerase II-mediated mechanisms and chr20 interactions. NKX2-4 plays developmental roles in central nervous system ventral region specification and organ development, particularly in thyroid organogenesis where it is required for early thyroid specification and cell fate commitment 2. In the embryonic brain, NKX2-4 transcription is activated through H2A.z-mediated epigenetic regulation, promoting neurogenesis and neuronal differentiation 3. NKX2-4 is increasingly recognized for disease relevance in hematologic and solid malignancies. In acute myeloid leukemia (AML), aberrant NKX2-4 expression disrupts megakaryocytic-erythroid differentiation by repressing the master lineage factor FLI1 and activating endothelial signature genes 45. In cancer contexts, NKX2-4 demonstrates allele-specific binding at the TERT/CLPTM1L risk locus in uveal melanoma, where it suppresses TERT and CLPTM1L expression in an allele-dependent manner 6. Clinically, NKX2-4 DNA methylation is a promising biomarker for non-invasive bladder urothelial carcinoma diagnosis, with inclusion in a four-gene detection panel achieving 92.39% diagnostic accuracy 7. Additionally, NKX2-4 hypermethylation has been identified in salivary gland adenoid cystic carcinoma 8, suggesting broader tumor suppressor functions.