PKNOX1 (PBX/knotted 1 homeobox 1) is a homeodomain-containing transcription factor that functions as a transcriptional activator, particularly in cooperation with PBX proteins 1. The protein contains 436 amino acids and belongs to the TALE (three-amino-acid loop extension) homeodomain family, showing close homology to mouse Meis1 and plant Knotted1 proteins 1. PKNOX1 activates transcription through sequence-specific DNA binding and requires cofactors like PBX1A and HOXA1 for optimal activity. The gene is located on chromosome 21.3 and undergoes alternative splicing to produce multiple isoforms, including PKNOX1B which lacks 30 amino acids at the C-terminus 2. PKNOX1 shows broad tissue expression and plays roles in development and cellular regulation 12. In disease contexts, PKNOX1 has emerged as a potential cancer biomarker, showing overexpression across multiple tumor types and association with poor prognosis 3. The protein promotes cancer cell proliferation, migration, and invasion in hepatocellular carcinoma and breast cancer 3. Additionally, PKNOX1 contributes to acute kidney injury through interaction with PKM2 and regulation of ferroptosis pathways 4. In neurological contexts, PKNOX1 binding sites are enriched for neuropsychiatric disorder risk variants, and the gene functions as a dosage-sensitive hub in Down syndrome, where chromosome 21 trisomy disrupts neurodevelopmental programs 56.