HOXB5 is a sequence-specific transcription factor that functions as a developmental regulator specifying cell identity along the anterior-posterior axis 1. During normal development, HOXB5 directly regulates neural crest specification genes (Sox9, Foxd3) and the RET gene, which is critical for enteric nervous system development 12. HOXB5 binds conserved sequences in the RET promoter and first intron, enhancing transcription through chr17 remodeling and histone H3K4 trimethylation 2. Mutations or dysregulation of HOXB5-mediated RET expression can cause Hirschsprung disease 2. HOXB5 also promotes human meiosis initiation when overexpressed in iPSCs alongside other factors 3. In cancer biology, HOXB5 predominantly functions as an oncogene with context-dependent dual roles 4. In gastric cancer, HOXB5 overexpression directly activates β-catenin transcription, promoting invasion and migration through Wnt signaling 5. Similarly, in hepatocellular carcinoma, HOXB5 transcriptionally activates EGFR, driving proliferation and migration; miR-200a-3p and miR-181-5p regulate HOXB5 expression 6. In castration-resistant prostate cancer, HOXB5 drives small cell carcinoma lineage plasticity 7. However, HOXB5 can suppress certain myeloid malignancies through immunological mechanisms 4. These findings establish HOXB5 as a multifunctional transcriptional regulator with significant clinical implications across developmental, reproductive, and neoplastic contexts.