HMX3 is a transcription factor of the H6 family that functions as a sequence-specific DNA-binding regulator of RNA polymerase II transcription 1. Developmentally, HMX3 is essential for inner ear morphogenesis, particularly controlling semicircular canal formation, and is required for hypothalamic-pituitary axis development 2. The gene is expressed in vestibular tissues and knockout mouse models demonstrate its necessity for normal vestibular function 2. Mechanistically, HMX3 establishes cell identity through mutually repressive interactions with other transcription factors. In kidney collecting ducts, HMX3 and HMX2 antagonistically regulate intercalated cell subtype specification; HMX3 promotes type B intercalated cell differentiation while being suppressed by Dmrt2, which instead promotes type A cell fate 3, 4. Post-translationally, USP38 directly interacts with HMX3 to stabilize its protein levels via deubiquitination 5. Clinically, HMX3 dysregulation is implicated in multiple disease contexts. In pediatric acute myelomonocytic leukemia with KMT2A::MLLT3 fusion lacking MECOM expression, HMX3 functions as a leukemia-specific vulnerability by driving cancer-associated E2F and MYC programs; HMX3 silencing induces cell cycle arrest and apoptosis 1. In colorectal cancer, HMX3 is significantly downregulated and acts as a tumor suppressor; overexpression suppresses proliferation, migration, and invasion while correlating with improved patient survival 5. Rare HMX3 variants associate with non-syndromic vestibular dysfunction and potentially superior semicircular canal dehiscence 2, 6.