RNASEK (ribonuclease K) is a highly conserved transmembrane endoribonuclease with multifaceted cellular roles. Primary function: RNASEK is required for viral entry across diverse enveloped viruses including dengue, West Nile, influenza, and coronavirus (PEDV), functioning as a host factor that facilitates clathrin-mediated endocytosis by interacting with viral structural proteins and promoting internalization 12. Mechanism: RNASEK localizes to early/late endosomes and endoplasmic reticulum 3. It is a component of the V-ATPase complex and mediates lysosomal hydrolase delivery, specifically PLD3 targeting via the ESCRT-III pathway, which is essential for autophagosome degradation and cargo clearance 4. RNASEK also directly degrades circular RNAs in stress granules, preventing age-associated circRNA accumulation 5. Disease relevance: RNASEK upregulation correlates with enhanced viral replication and is a diagnostic biomarker in six cancer types (bladder, cholangiocarcinoma, esophageal, head/neck squamous cell, liver, thyroid) 6. High expression predicts favorable prognosis in pancreatic adenocarcinoma 6. In bone metastasis, RNASEK expression is upregulated via DKK1/LRP5 signaling to promote osteoclast precursor recruitment 7. Clinical significance: RNASEK represents a potential therapeutic target for antiviral and cancer interventions, with soluble receptor-based inhibition strategies showing promise in bone metastasis models 72.