PRSS8 (serine protease 8) is a membrane-anchored trypsin-like serine protease located on chromosome 16.2 1. Its primary function involves activating the epithelial sodium channel (ENaC) through proteolytic cleavage of gamma subunits, facilitating sodium ion transport in epithelial tissues. Mechanistically, PRSS8 exerts multiple regulatory effects through protease activity and cell signaling modulation. The protein acts as a tumor suppressor across multiple cancer types (colorectal, hepatocellular, and lung cancers), where it suppresses Wnt/β-catenin signaling, epithelial-mesenchymal transition (EMT), and stem cell pathways 234. In esophageal squamous cell carcinoma, PRSS8 expression is epigenetically silenced through promoter hypermethylation, and restoration of expression via demethylation inhibits cancer cell proliferation and migration 5. Disease relevance extends beyond cancer: PRSS8 is implicated in neurodegenerative diseases through microglia-associated pathways in Alzheimer's disease 6, and serves as a predictive biomarker for Crohn's disease up to 16 years before symptom onset 7. In psoriatic disease, elevated PRSS8 levels substantially increase disease risk, with in vivo gene silencing reducing skin lesions and inflammatory markers 8. Clinically, PRSS8 represents a valuable prognostic marker and potential therapeutic target across multiple diseases, with tumor suppressor functions and predictive capacity for early disease intervention.