PBX3 is a homeobox transcription factor that functions as a DNA-binding transcriptional activator, recognizing the sequence 5'-ATCAATCAA-3'. It belongs to the pre-B-cell leukemia homeobox family and shares 94% amino acid identity with PBX1 over the homeodomain region 1. Unlike PBX1, PBX3 is widely expressed across fetal and adult tissues 1. In normal development, PBX3 plays roles in neurodevelopment and lineage specification. Chr9 glucocorticoid exposure during neural differentiation upregulates PBX3, which primes inhibitory neuron lineage specification in human neural organoids 2. This suggests PBX3 mediates developmental responses to environmental signals. In cancer pathogenesis, PBX3 is frequently dysregulated and promotes malignancy through multiple mechanisms. It enhances cell proliferation by modulating cell cycle progression and inhibits apoptotic pathways, promoting tumor cell survival 3. PBX3 also facilitates epithelial-mesenchymal transition and invasive potential 3. Elevated PBX3 expression correlates with poor prognosis in gliomas, particularly low-grade gliomas, and serves as an independent prognostic factor 4. MicroRNA-mediated PBX3 suppression inhibits proliferation and induces apoptosis in hepatocellular carcinoma and multiple myeloma 56. Additionally, PBX3 is transcriptionally regulated by ETV5 during neuroendocrine prostate cancer development, contributing to castration resistance and stemness 7. PBX3 represents a promising diagnostic biomarker and therapeutic target across multiple cancer types.