USP9X is an X-linked deubiquitinase that plays essential roles in cellular homeostasis and development by removing ubiquitin conjugates from target proteins. The enzyme exhibits substrate specificity, primarily cleaving K63-linked, K48-linked, and K11-linked polyubiquitin chains to regulate protein stability and function 1. USP9X is critical for TGF-β/BMP signaling through deubiquitination of SMAD4 and regulation of transforming growth factor β pathways 23. In the cardiovascular system, USP9X suppresses atherosclerosis by deubiquitinating scavenger receptor SR-A1 at K27, reducing foam cell formation 1, and protects against cardiac hypertrophy through MCL1 stabilization and mitochondrial homeostasis 4. The protein is essential for CNS development and function, regulating Wnt signaling via β-catenin deubiquitination to maintain vascular barrier integrity 5. USP9X also controls Nrf2 stability to prevent ferroptosis in diabetic kidney disease 6. Disease-associated variants cause intellectual developmental disorders in both males and females, with males showing distinctive neurodevelopmental phenotypes including white matter abnormalities, speech delays, and behavioral changes 2. The enzyme's diverse substrate specificity underlies its involvement in metabolic disorders, cancer radioresistance, and neurodegeneration 73.