PAX3 (paired box 3) is a transcription factor containing a highly conserved paired box motif and homeodomain that plays critical roles in development and disease 1. The protein consists of an N-terminal DNA-binding domain and a C-terminal transcriptional activation domain, functioning primarily as a transcriptional activator through two separate DNA-binding domains: the Paired Domain (PD) and Homeodomain (HD) 12. PAX3 is essential during embryonic development of skeletal muscle, central nervous system, and neural crest derivatives, regulating target genes that control proliferation, survival, differentiation, and cell motility 1. Loss-of-function mutations cause developmental defects including Waardenburg syndrome in humans, occurring through haploinsufficiency mechanisms 34. In cancer, PAX3 contributes to pathogenesis through chr2 rearrangements, particularly the PAX3-FOXO1 fusion in fusion-positive rhabdomyosarcoma (FP-RMS), an aggressive pediatric sarcoma 15. This fusion oncoprotein can reprogram non-myogenic cells like endothelial progenitors into malignant myogenic cells 5. PAX3-FOXO1 drives metabolic vulnerabilities in RMS cells, including increased dependence on pyrimidine synthesis enzymes like DHFR, making these tumors sensitive to methotrexate treatment 6. Wild-type PAX3 is also overexpressed in various cancers including melanoma and neuroblastoma, where it promotes oncogenic cellular behaviors 17.