ATP4B encodes the β-subunit of the gastric H+/K+-ATPase proton pump, which transports H+ ions in exchange for K+ ions across the apical membrane of parietal cells 1. The protein functions as a structural and regulatory component that stabilizes the pump in its outward-facing (E2) conformation, preventing reverse transport and ensuring efficient gastric acid secretion [UniProt annotation]. ATP4B expression is progressively downregulated in gastric pathology, including atrophic gastritis, intestinal metaplasia, and early gastric cancer, correlating with malignant transformation and poor tumor differentiation 213. Molecular silencing of ATP4B in gastric cancer involves intragenic DNA hypermethylation and histone deacetylation, mechanisms reversible by epigenetic inhibitors 45. Functionally, ATP4B acts as a tumor suppressor—its restoration suppresses gastric cancer cell proliferation, migration, and invasion while inducing apoptosis through regulation of mitochondrial metabolism 1. Clinically, ATP4B serves multiple roles: methylated ATP4B DNA in plasma is a potential gastric cancer biomarker 4, autoantibodies against ATP4B distinguish corpus atrophic gastritis with superior diagnostic performance (AUC 0.838) compared to pepsinogen I 6, and ATP4B downregulation correlates with mucosal acidity compromise detectable by novel AI-assisted pH mapping systems for early cancer detection 3.