TERF2IP (RAP1) is a multifunctional shelterin complex component with dual roles in telomere maintenance and transcriptional regulation. At telomeres, TERF2IP negatively regulates homology-directed repair and represses telomere recombination, though it is dispensable for telomeric capping 1. Biochemically, TERF2IP forms a complex with TRF2 and DNA-PK that directly inhibits non-homologous end joining at chromosome 16, establishing a context-specific mechanism for chromosome 16 protection 1. Beyond telomeric functions, TERF2IP acts as a transcription regulator at extratelomeric sites and regulates NF-κB signaling via IKK complex association, promoting RELA/p65 phosphorylation 2. Clinically, germline TERF2IP mutations predispose to familial melanoma, representing one of several high-penetrance melanoma predisposition genes alongside CDKN2A, CDK4, and BAP1 34. Recent evidence reveals TERF2IP's hepatoprotective role: deficiency accelerates non-alcoholic steatohepatitis by impairing lipophagy and fatty acid oxidation through the Sirt1/AMPK pathway, and Terf2ip downregulation occurs in NASH patient livers 5. TERF2IP also functions as a multifunctional player in cancer development and chemoresistance across various malignancies 2. These findings position TERF2IP as both a cancer susceptibility gene and a potential therapeutic target for metabolic and malignant diseases.