CLCA4 (chloride channel accessory 4) functions as a calcium-activated chloride channel regulator that modulates ion transport across cell membranes. The protein is a self-cleaving metalloprotease that releases an N-terminal fragment containing a von Willebrand factor type A (VWA) domain, which is sufficient to potentiate calcium-dependent chloride currents 1. CLCA4 specifically interacts with TMEM16B channels, distinct from CLCA1's interaction with TMEM16A, demonstrating specificity in CLCA/TMEM16 protein family interactions 1. The gene shows tissue-specific expression patterns, with normal colonocytes expressing CLCA4 while small intestine enterocytes do not 2. In disease contexts, CLCA4 functions as a tumor suppressor in multiple cancers. Expression is frequently downregulated in colorectal cancer, with frameshift mutations occurring in 11.8% of microsatellite instability-high cases but not in microsatellite stable tumors 3. Loss of CLCA4 expression correlates with poor prognosis in colorectal cancer and hepatocellular carcinoma 45. Mechanistically, CLCA4 inhibits epithelial-to-mesenchymal transition via PI3K/AKT signaling, thereby suppressing cancer cell migration and invasion 5. The protein also shows associations with immune infiltration in colon adenocarcinoma 6.