WWOX (WW domain containing oxidoreductase) is a large tumor suppressor gene spanning over 1.11 Mbp at chromosome 16.1-q23.2, containing the common fragile site FRA16D 1. The gene encodes a 46 kDa protein with 414 amino acids that functions as a putative oxidoreductase and transcription regulator 23. WWOX acts as a tumor suppressor through multiple mechanisms, including transcriptional repression and apoptosis induction, with interactions involving c-Jun, TNF, p53, p73, and other key regulatory proteins 2. The protein plays critical roles in cellular senescence and genome stability maintenance by inducing DNA damage response mechanisms and preventing senescence escape 4. WWOX is essential for normal central nervous system development, with mutations causing seizures, ataxia, developmental delay, and spasticity 5. The gene also regulates metabolic processes, including steroid, cholesterol, and glucose metabolism, with deficiency linked to familial dyslipidemias and metabolic syndrome 67. In cancer, WWOX deletions are frequent in esophageal, stomach, colon, bladder, ovarian, and uterine cancers, correlating with poor prognosis and therapy resistance 1. Recent studies demonstrate WWOX's role in immune regulation, where deficiency promotes immunosuppressive macrophage polarization and reduces sensitivity to immunotherapy in hepatocellular carcinoma 8.