HVCN1 encodes a voltage-gated proton-selective channel that conducts outward proton currents in response to intracellular acidification and lacks a canonical pore domain, instead mediating proton permeability through its voltage sensor domain 1. The channel plays critical roles in multiple physiological processes. In neutrophils, HVCN1 provides essential charge compensation during the NADPH oxidase-mediated respiratory burst, preventing excessive alkalinization of phagocytic vacuoles and cytosolic acidification that would otherwise impair bacterial killing 2. The channel optimizes reactive oxygen species production by balancing electron transport across membranes and providing substrate protons for bactericidal compounds 1. HVCN1 also regulates pH homeostasis in sperm flagella, maintaining bicarbonate levels necessary for capacitation 3, and facilitates acid secretion in respiratory epithelium when airway pH exceeds 7 1. Disease relevance includes potential therapeutic targeting in amyotrophic lateral sclerosis, where microglial HVCN1 deletion improves motor neuron survival and extends lifespan in mouse models 4. The channel also shows altered expression in inflammatory conditions like Crohn's disease 5 and has been identified as a potential migraine therapeutic target 6. HVCN1's unique properties, including perfect proton selectivity and pH-dependent gating, make it an attractive target for treating autoimmune and neurodegenerative diseases 3.