TMPRSS15 (transmembrane serine protease 15), also known as enterokinase, is a brush border serine protease primarily responsible for initiating activation of pancreatic proteolytic proenzymes. It catalyzes conversion of trypsinogen to trypsin, which subsequently activates other digestive proenzymes including chymotrypsinogen and procarboxypeptidases 1. Beyond its canonical digestive role, TMPRSS15 regulates intestinal nutrient absorption, including ions such as sodium, potassium, and potentially lithium 1. Recent evidence suggests TMPRSS15 variants modulate lithium response in bipolar disorder through altered intestinal lithium absorption 1. The enzyme also enhances influenza A virus infection by activating trypsinogen, which processes viral hemagglutinin 2. Loss-of-function mutations cause enterokinase deficiency (EKD), a rare autosomal recessive disorder presenting with acrodermatitis enteropathica-like skin lesions and digestive dysfunction 3. TMPRSS15 dysregulation has been identified in multiple malignancies, including ovarian carcinoma and esophageal squamous cell carcinoma, where altered expression correlates with chemoresistance and tumor progression [PMID:26318424; 48]. Additionally, TMPRSS15 variants have been detected in severe COVID-19 cases with hemophagocytic lymphohistiocytosis, suggesting roles in immune regulation 5. Genetic studies link TMPRSS15 variants to subcortical brain volume variation in PTSD 6.