ZHX3 is a ubiquitously expressed zinc finger and homeobox transcription factor that functions primarily as a transcriptional repressor 1. It contains two C2H2-type zinc finger motifs and five homeodomains, enabling heterodimerization with ZHX1 and ZHX2, as well as homodimerization 12. ZHX3 regulates multiple cellular processes through DNA binding at promoter regions and interaction with cofactors like CEBPB and NF-YA. Mechanistically, ZHX3 represses gluconeogenic genes (PCK1, G6PC1) in hepatocytes and suppresses uric acid transporter expression via CEBPB interaction, thereby regulating glucose metabolism and fasting blood glucose levels 3. In podocytes, nuclear localization of ZHX3 is regulated by heterodimerization status, with reduced nuclear sequestration associated with nephrotic syndrome development 4. ZHX3 loss induces cellular senescence through upregulation of senescence-associated genes like p16INK4a and ribosomal RNA genes 5. Clinically, ZHX3 demonstrates context-dependent roles: it promotes early mesenchymal stem cell osteogenic differentiation and serves as an osteogenic marker 6, yet functions as an oncogene in urothelial bladder carcinoma by repressing RGS2 and promoting cell migration and invasion 7. SNP associations with type 2 diabetes risk reflect ZHX3's metabolic regulatory function 3, positioning it as a therapeutic target in both metabolic and neoplastic diseases.