PRSS3 (serine protease 3) is a digestive protease that cleaves proteins preferentially after arginine residues and degrades trypsin inhibitors 1. The gene encodes multiple isoforms, including trypsinogen variants with distinct leader peptides that are not secreted from cells 2. In cancer biology, PRSS3 functions as an oncogenic driver with context-dependent roles. In pancreatic cancer, PRSS3 overexpression promotes tumor growth and metastasis by upregulating VEGF expression via PAR1-mediated ERK signaling 3. In breast cancer, the PRSS3-V1 isoform drives malignancy by activating PAR2 and enhancing ERK1/2 phosphorylation, while also suppressing ferroptosis through downregulation of key ferroptosis regulators 4. PRSS3 similarly promotes lung adenocarcinoma invasion and proliferation, with expression associated with poor prognosis 5. Importantly, shear stress in circulating tumor cells triggers PRSS3-mediated PAR2 cleavage to promote metastasis 6. Conversely, in hepatocellular carcinoma, PRSS3 acts as a tumor suppressor; its epigenetic silencing via intragenic hypermethylation promotes HCC growth and metastasis by activating ERK signaling 7. Genetic variants in PRSS3 showed no association with chr9 pancreatitis risk 1, and recent data implicate PRSS3-F2R pathway signaling in psoriatic inflammation 8.