DDX3X is an X-linked DEAD-box RNA helicase with critical roles in RNA metabolism, cellular stress responses, and neurodevelopment. Mechanistically, DDX3X regulates multiple stages of RNA processing and acts as a molecular rheostat controlling cell fate decisions 1. Under stress conditions, DDX3X coordinates between stress granule assembly and NLRP3 inflammasome activation; stress granule formation sequesters DDX3X to inhibit inflammasome-mediated pyroptosis, allowing cells to survive stress 2. In neural development, DDX3X controls cortical neurogenesis by regulating translation and RNA metabolism; pathogenic missense mutations impair RNA helicase activity, induce aberrant RNA-protein granules, and disrupt translation, leading to brain malformations including polymicrogyria 3. Clinically, DDX3X mutations account for 1-3% of unexplained intellectual disability cases in females 3, causing DDX3X syndrome—a neurodevelopmental disorder characterized by intellectual disability, autism spectrum disorder, language delays, ADHD, and neurological/psychiatric comorbidities affecting ~200 described individuals 4. Notably, DDX3X shows female-biased de novo mutation enrichment in neurodevelopmental disorders 5, suggesting sex-specific vulnerability. DDX3X mutations also contribute to cancer pathogenesis and various malignancies 1, though specific mechanisms in pediatric cancers require further elucidation.