UPF3B is a core component of the nonsense-mediated mRNA decay (NMD) pathway that protects cells from potentially harmful transcripts containing premature termination codons 1. As an X-linked gene, UPF3B functions by associating with the nuclear exon junction complex (EJC) and recruiting UPF2 to form a surveillance complex with UPF1 that activates NMD of aberrant mRNAs 2. However, UPF3B operates with functional redundancy alongside its paralog UPF3A; depletion of both proteins substantially inhibits NMD, while either protein alone maintains partial activity 2. Notably, NMD activation by UPF3B is largely independent of EJC binding, instead depending on conserved mid-domain interactions with other NMD factors 3. Hemizygous variants in UPF3B cause X-linked neurodevelopmental disorder (XL-NDD) presenting with intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia 1. Clinical features include cognitive impairment, central hypotonia, microcephaly, and brain malformations 1. Beyond developmental disorders, aberrant UPF3B splicing contributes to hepatocellular carcinoma metastasis and gastric cancer progression through altered mRNA regulation 45. These findings establish UPF3B as both a critical guardian against genomic instability and a gene whose dysregulation contributes to neuropsychiatric and malignant disease.