OTOP3 (otopetrin 3) encodes a proton-selective ion channel that is gated by extracellular protons and modulated by zinc ions 12. The channel exhibits pH-dependent activation, showing no significant activity at physiological pH (7.4) or mildly acidic conditions (pH 6.5), but can be activated by Zn2+ under these conditions without zinc permeation through the channel 2. OTOP3 belongs to an evolutionarily conserved gene family (OTOP1-3) with homologs in Drosophila, suggesting broad physiological roles 1. In colorectal cancer, OTOP3 functions as an oncogenic regulator by enhancing c-Myc protein stability and inhibiting ferroptosis through GPX4 regulation 3. OTOP3 downregulation is associated with colorectal adenoma compared to hyperplastic polyps 4, and its expression levels serve as a prognostic biomarker in stage IV colorectal cancer patients 56. The protein's role in cancer progression involves suppressing ferroptosis-mediated cell death while promoting metabolic reprogramming characteristic of the Warburg effect 3. These findings position OTOP3 as both a fundamental proton channel and a potential therapeutic target in colorectal cancer treatment.