IRX4 (Iroquois homeobox 4) is a ventricle-restricted homeobox transcription factor that functions as a critical mediator of cardiac ventricular differentiation during development 1. The gene encodes a DNA-binding transcription factor whose cardiac expression is modulated downstream of cardiac transcription factors Nkx2-5 and dHand 1. IRX4 expression is predominantly restricted to ventricular myocardium from embryonic stages through adulthood, with minimal expression in atrial or outflow tract regions 1. Structurally, the IRX4 homeodomain contains conserved amino acid residues critical for DNA binding and protein-DNA complex stability, with specific residues (R145, R198, R199) essential for interaction with consensus DNA sequences 2. Clinically, IRX4 mutations are associated with congenital heart disease, particularly ventricular septal defects 3. Identified disease-causing mutations (p.Asn85Tyr and p.Glu92Gly) significantly impair IRX4 interaction with RXRA, suggesting a causative role in cardiac developmental pathology 3. Beyond cardiac development, IRX4 functions as a tumor suppressor in multiple cancer types. In prostate cancer, IRX4 suppresses cell growth through interaction with the vitamin D receptor pathway 4, while in colorectal cancer, IRX4 overexpression inhibits proliferation and enhances chemosensitivity to oxaliplatin by suppressing NF-κB/EGFR signaling 5. Alternative splicing generates multiple IRX4 isoforms with distinct functional properties relevant to cancer progression 6.