SLC26A3 (Down-Regulated in Adenoma, DRA) is a Na+-independent chloride-bicarbonate exchanger mediating 2:1 Cl-/HCO3- exchange at the apical membrane of intestinal epithelial cells 1. This transporter plays a critical role in electroneutral NaCl absorption and acid-base homeostasis in the gastrointestinal tract 2. Beyond ion transport, SLC26A3 maintains intestinal epithelial barrier integrity by supporting tight junction protein expression (ZO-1, occludin, E-cadherin) 3 and enables mucin barrier formation through bicarbonate supply 4. Loss-of-function SLC26A3 mutations cause congenital chloride diarrhea (CLD), characterized by severe secretory diarrhea, dehydration, and electrolyte imbalance 1. Additionally, SLC26A3 downregulation occurs in multiple gastrointestinal disorders including inflammatory bowel disease (IBD) and infectious diarrhea caused by enteropathogens 5. Emerging evidence identifies SLC26A3 as an IBD susceptibility gene 3. Therapeutic upregulation via probiotics or butyrate enhances DRA expression and function through ERK1/2 MAPK and HDAC8 inhibition pathways, respectively, improving barrier integrity and reducing inflammation 6, 7. SLC26A3 is recognized as a high-priority therapeutic target for diarrheal diseases and IBD 8.