OTOP2 is a proton-selective ion channel expressed in specialized intestinal epithelial cells that functions as a pH sensor and regulator of luminal pH. The channel conducts protons across cell membranes and is active at neutral and alkaline extracellular pH 1. Structurally, OTOP2 forms a dimer with a double-barrel architecture; proton conduction occurs through an inter-barrel, Glu/His-bridged pathway within each subunit, with inter-subunit movements at the dimer interface regulating channel activity 2. OTOP2 is a marker gene of BEST4+ absorptive cells, a recently identified human intestinal epithelial cell lineage absent in mice 3. These specialized cells likely function in pH sensing, electrolyte secretion, and innate immune defense. Clinically, OTOP2 hypermethylation in circulating cell-free DNA serves as a diagnostic biomarker for esophageal cancer detection, with blood-based assays targeting OTOP2 methylation achieving 87.4% sensitivity and 93.3% specificity 45. In inflammatory bowel disease, BEST4+OTOP2+ cells are reduced during active ulcerative colitis and associate with myeloid cell infiltration and anti-TNF therapy non-response 61. Rare OTOP2 variants have been identified in patients with Meniere's disease 7. Small molecule allosteric modulators selectively target OTOP1 while sparing OTOP2, indicating distinct pharmacological properties among otopetrin family members 8.