CCDC137 (coiled-coil domain containing 137) is a nuclear protein with RNA-binding and epigenetic regulatory functions that plays multifaceted roles in viral pathogenesis and cancer progression. As a primary function, CCDC137 acts as a nucleolar stress sensor and regulator of protein stability through ubiquitin-proteasome pathways 1. Mechanistically, CCDC137 operates through distinct pathways depending on cellular context: HIV-1 Vpr targets CCDC137 for CRL4A-dependent degradation, inducing G2/M cell cycle arrest and enhancing viral gene expression 2, while a nucleolar ATR pathway mediates CCDC137 degradation in response to genomic stress 1. In cancer, CCDC137 promotes hepatocellular carcinoma (HCC) progression by facilitating LZTS2 ubiquitination through β-TrCP recruitment, activating β-catenin and AKT signaling 3, and promotes aerobic glycolysis via the CCDC137/DGCR8-AKT/mTOR axis 4. CCDC137 similarly drives bladder cancer progression by regulating stearoyl-CoA desaturase (SCD) expression 5 and colorectal cancer hepatic metastasis through super-enhancer-associated transcription 6. Clinically, CCDC137 overexpression correlates with poor prognosis across multiple cancer types and represents a pan-cancer biomarker 78. Therapeutic targeting of CCDC137 through peptide disruption of protein-protein interactions shows promise in HCC models 3.