BEST4 encodes a calcium-activated anion channel that mediates the movement of chloride and bicarbonate ions across cell membranes. The protein functions as a ligand-gated anion channel activated by intracellular calcium, allowing anion transport at the plasma membrane. BEST4 is expressed as a marker of a recently identified mature absorptive epithelial cell lineage distributed throughout the human small and large intestine at low abundance (<5% of epithelial cells) 1. BEST4+ intestinal cells co-express additional marker genes including OTOP2, CA7, GUCA2A, GUCA2B, and SPIB, with location-specific gene expression profiles suggesting functional specialization across gut regions 1. In the small intestine, BEST4+ cells express CFTR, an ion channel regulating fluid secretion 2. Recent experimental work demonstrates that BEST4/CA7+ cells generate robust CFTR-mediated fluid efflux in response to bacterial diarrhea-causing toxins, and their numbers increase following interferon-γ stimulation, supporting a role in immune-mediated fluid homeostasis 3. BEST4 variants associate with colorectal adenoma and cancer, consistent with its expression in intestinal epithelium. The gene's functions appear to include electrolyte transport, pH sensing, and antimicrobial defense, though most functional roles remain incompletely validated in human disease contexts 1. BEST4+ cells are absent in mice, limiting disease modeling in conventional animal systems.