BEST4 (bestrophin 4) encodes a calcium-activated anion channel that plays multiple roles in intestinal epithelial function and disease. BEST4 functions as a ligand-gated anion channel activated by calcium, mediating the movement of bicarbonate and chloride across cell membranes 12. In the human intestinal tract, BEST4 defines a distinct subpopulation of mature absorptive epithelial cells (BEST4+ cells) present throughout the small and large intestine at low abundance (<5% of epithelial cells) 3. These cells show region-specific gene expression profiles, with small intestine-specific expression of CFTR suggesting functional specialization 43. BEST4+ cells are predicted to regulate luminal pH, electrolyte transport, mucus hydration, and antimicrobial peptide secretion 3. Recent functional studies demonstrate that BEST4+ cells generate robust CFTR-mediated fluid efflux when stimulated with bacterial toxins and respond strongly to interferon-γ, supporting roles in fluid homeostasis and immunity 5. In colorectal cancer, BEST4 acts as a tumor suppressor by inhibiting epithelial-to-mesenchymal transition through downregulation of TWIST1, with low BEST4 expression correlating with poor prognosis 6. BEST4+ cells are notably absent in mice but present in other species including zebrafish, macaque, and pig 3.