NKX3.1 is an androgen-regulated homeodomain transcription factor that serves as a critical regulator of prostate development and tumor suppression 12. The protein functions as a pioneer factor, binding to chr8 at enhancers to integrate androgen-regulated signaling pathways in prostate epithelial cells 3. NKX3.1 acts primarily as a transcriptional repressor and plays essential roles in normal prostate organogenesis, regulating epithelial proliferation and ductal formation 1. In prostate cancer, NKX3.1 functions as a tumor suppressor, with its loss representing an initiating event in carcinogenesis 12. The protein directly binds to TMPRSS2 promoter sequences and negatively regulates ERG oncogene expression through TMPRSS2-ERG gene fusions, a common mechanism in prostate cancer progression 4. NKX3.1 expression is frequently reduced in prostate cancer through multiple mechanisms including allelic loss, haploinsufficiency, and post-translational modifications that affect protein stability 54. Single-cell analysis has revealed that NKX3.1-positive differentiated luminal cells contribute significantly to prostate regeneration following androgen deprivation 6. Due to its prostate specificity, NKX3.1 serves as a valuable immunohistochemical marker in clinical practice, though rare expression in non-prostatic tumors has been documented 37.