WWOX in brain development and disease: Molecular mechanisms and therapeutic opportunities.

The WW domain-containing oxidoreductase (WWOX) gene, located at the common fragile site FRA16D, has emerged as a key molecular link between genome instability and nervous system biology. Initially identified as a tumor suppressor frequently disrupted in cancer, WWOX is now recognized as a multifunctional signaling scaffold that integrates pathways governing DNA damage responses, transcriptional regulation, cellular metabolism, and neuronal differentiation. Genetic studies have revealed that germline WWOX mutations cause a severe developmental and epileptic encephalopathy, known as WWOX-related epileptic encephalopathy (WOREE syndrome), characterized by early-onset seizures, profound neurodevelopmental impairment, and early mortality. Beyond this rare neurodevelopmental disorder, accumulating evidence implicates WWOX dysfunction in broader neurological conditions, including autism spectrum disorder and major neurodegenerative diseases. Mechanistic studies using mouse models and human brain organoids demonstrate that WWOX loss disrupts neuronal maturation, alters excitatory-inhibitory circuit balance, impairs oligodendrocyte development, and induces widespread transcriptional and metabolic dysregulation. Importantly, restoration of neuronal WWOX expression using AAV-based gene therapy rescues seizures, myelination defects, and survival in preclinical models, highlighting the translational potential of WWOX replacement strategies. In this Review, we discuss how fragile-site biology led to the discovery of WWOX, examine its molecular functions in neuronal homeostasis, and explore emerging therapeutic avenues targeting WWOX-related neurological disease.