CAPNS1 encodes the regulatory small subunit of calpain proteases, which are calcium-dependent cysteine proteases essential for cellular functions. 1 This 28-kDa protein stabilizes and activates both μ- and m-calpain catalytic subunits, which contain the proteolytic activity. 2 CAPNS1 regulates diverse cellular processes including cytoskeletal remodeling, focal adhesion dynamics, autophagy, apoptosis, and cell migration. 2 Mechanistically, calpain-mediated proteolysis targets proteins like talin-1, vinculin, and integrin-alpha-V, modulating endothelial integrity and cell-cell adhesion. 3 Clinically, CAPNS1 dysregulation associates with multiple pathologies. Endothelial-specific CAPNS1 deletion mitigates thoracic aortic dissection by preventing focal adhesion disruption and endothelial barrier dysfunction. 3 In cancer, elevated CAPNS1 promotes cisplatin resistance in gastric cancer by suppressing caspase-3-mediated apoptosis and can be suppressed by miR-99a and miR-491. 4 CAPNS1 overexpression correlates with poor prognosis in renal cell carcinoma, promoting invasion and metastasis through increased MMP2/9 expression. 5 In type 2 diabetes, CAPNS1 upregulation drives junctophilin-2 cleavage and cardiac dysfunction. 6 Emerging evidence identifies CAPNS1 as a vesicular biomarker for HBV-associated hepatocellular carcinoma detection. 7