HOMEZ (homeobox and leucine zipper encoding) is a vertebrate-specific transcriptional regulator located on chromosome 14.2 1. The gene encodes a multi-domain protein containing three atypical homeodomains, two leucine zipper-like motifs, and an acidic domain, exhibiting DNA-binding transcription factor activity specific to RNA polymerase II 1. HOMEZ is ubiquitously expressed across human tissues, though with restricted expression patterns during mouse development 1. Mechanistically, HOMEZ functions as a transcriptional co-regulator within the chr14 landscape, with its homeodomain and leucine zipper motifs enabling DNA binding and protein-protein interactions 1. The protein shares structural similarities with the ZHX family of zinc finger homeodomain factors, representing a distinct subfamily within homeobox-containing proteins 1. Clinically, HOMEZ variants associate with congenital heart disease (CHD), particularly ventricular septal defects (VSD). Two novel heterozygous missense mutations (c.116C>T and c.630T>A) in Chinese VSD patients altered protein hydropathicity at conserved positions, suggesting pathogenic effects 2. Additionally, HOMEZ linkage was identified in consanguinity mapping of CHD in Indian populations 3. Recently, HOMEZ emerged as part of a five-gene signature predicting multiple myeloma risk under bortezomib-based therapy, indicating broader oncological relevance 4. HOMEZ is also targeted by miR-155 in B-cell lymphoma pathogenesis 5.