TMPRSS9 (transmembrane serine protease 9), also known as polyserase-1, is a type II transmembrane serine protease with three tandem protease domains 1. It functions as a serine-type peptidase that hydrolyzes specific peptide substrates and activates urokinase-type plasminogen activator (pro-uPA) 2. TMPRSS9 is widely expressed across tissues including brain, liver, intestine, pancreas, and immune cells, with expression patterns varying by sex and physiological conditions 342. Disease relevance spans multiple systems. In neuropsychiatric conditions, loss-of-function TMPRSS9 variants associate with autism spectrum disorder, with knockout mice demonstrating decreased social interest and recognition memory deficits 3. TMPRSS9 variants also associate with neuroticism and bipolar disorder through genome-wide association studies 56. In cancer, TMPRSS9 promotes pancreatic cancer cell invasiveness and anchorage-independent growth via pro-uPA activation and ERK phosphorylation, suggesting anti-TMPRSS9 therapy may inhibit tumor progression 1. Additionally, TMPRSS9 serves as a sex-specific modifier of serum potassium handling in women and associates with respiratory symptoms in occupational exposure contexts 47. The protein functions as a marker for inner ear progenitor cell differentiation 8. Its regulation by glycosaminoglycans and natural protease inhibitors suggests homeostatic mechanisms controlling proteolytic activity 2.