DUX4 is an early embryonic transcription factor that normally drives cleavage-stage gene expression and retrotransposon activation during preimplantation development 1. The protein functions as a DNA-binding transcription factor capable of activating hundreds of endogenous genes including ZSCAN4, KDM4E, and PRAMEF-family genes, as well as MERVL/HERVL retroviral elements 1. DUX4 also interacts with STAT1 to suppress interferon-stimulated gene expression, modulating immune signaling pathways 2. Pathologically, DUX4 misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD), one of the most common muscular dystrophies 3. FSHD arises from derepression of DUX4 due to contraction of D4Z4 macrosatellite repeats on chromosome 4 or, in FSHD2, mutations in SMCHD1 affecting chr4 regulation 4. The resulting DUX4 toxicity causes progressive, asymmetric muscle weakness affecting facial, shoulder girdle, and extremity muscles, with extramuscular manifestations including pain, fatigue, and in severe cases, hearing loss and cognitive impairment 3. DUX4 fusion genes also drive aggressive malignancies, including CIC-DUX4 sarcomas (characterized by CIC::DUX4 translocations causing ETV4 overexpression) and DUX4-rearranged acute lymphoblastic leukemia 56. Currently, FSHD lacks curative therapies, though disease-modifying clinical trials targeting DUX4 are emerging 3.