DUXA is a transcription factor containing a double homeobox DNA-binding domain that functions primarily as a transcriptional repressor 1. Unlike its paralog DUX4, DUXA lacks intrinsic transcriptional activation capacity but shares substantial DNA-binding overlap with DUX4 on target genes including zygotic genome activation (ZGA) genes and long terminal repeat elements 12. DUXA acts as a competitive inhibitor of DUX4, antagonizing DUX4 activity on shared targets including in facioscapulohumeral muscular dystrophy (FSHD) patient cells 12. Since DUXA is itself a DUX4 target gene, this antagonism creates a feedback mechanism that constrains the temporal window of DUX4 activity 12. In FSHD myotubes, DUXA is more widely expressed than DUX4 and can maintain target gene expression independently, particularly in late differentiation stages, suggesting it sustains a self-perpetuating network of gene dysregulation after initial DUX4 activation 34. DUXA is transiently expressed during normal preimplantation embryonic development 5 and its dysregulation has been implicated in early embryonic arrest 6. Additionally, DNA methylation at the DUXA locus may mediate associations between prenatal endocrine-disrupting chemical exposure and childhood obesity 7.