CAPN8 (calpain 8) is a calcium-dependent cysteine protease primarily involved in gastric mucosal homeostasis and cellular proteolysis. In normal physiology, CAPN8 functions in the gastric surface mucus pit cells, forming a functional complex with calpain 9 called G-calpain that is essential for gastric mucosal defense against ethanol-induced injury 1. The protein operates through proteolytic cleavage of coatomer complex components and participates in vesicle trafficking between the ER and Golgi 1. Beyond its gastric role, CAPN8 has emerged as a significant oncogenic factor across multiple cancer types. In thyroid cancer, elevated CAPN8 expression activates epithelial-mesenchymal transition (EMT) and E2F pathways, associating with an exhausted tumor immune microenvironment and metastatic potential 2. Similarly, in pancreatic cancer, CAPN8 overexpression correlates with poor prognosis and advanced TNM stage, operating through EMT and AKT/ERK signaling pathways 3. In lung adenocarcinoma, CAPN8 is identified as a malignant-cell-specific gene promoting proliferation 4, with upregulation occurring progressively across all adenocarcinoma stages 5. The gene also shows association with poor survival outcomes in lung cancer 6. Clinically, CAPN8 represents a promising diagnostic and prognostic biomarker across multiple malignancies, though its potential as a direct therapeutic target requires further validation 4.