PRSS2 (serine protease 2) is an anionic trypsinogen that functions as a serine-type endopeptidase involved in proteolysis and extracellular matrix disassembly 1. In the ileum, PRSS2 may participate in defensin processing. The protein exhibits calcium ion binding activity and operates in extracellular regions and azurophil granule lumens [GO annotations]. PRSS2 is causally associated with acute pancreatitis risk through a gene dosage mechanism. Increased PRSS2 expression correlates with elevated pancreatitis susceptibility 2, and common polymorphisms (rs10273639) significantly associate with both acute and chr7 pancreatitis across populations 3. The risk allele demonstrates an additive genetic model and synergistic interaction with alcohol consumption in chr7 pancreatitis 4. Genome-wide association studies identified PRSS2 variants among five loci linked to acute pancreatitis, with proteome-wide Mendelian randomization confirming causal associations 5. Beyond pancreatic disease, PRSS2 is upregulated in gastric cancer tissues where it promotes epithelial-mesenchymal transition and metastasis through MMP-9 signaling, correlating with poor prognosis 6. Downregulating pancreatic PRSS2 expression represents a potential therapeutic strategy for pancreatitis prevention, while PRSS2 may serve as a diagnostic biomarker in gastric cancer.