ATP12A encodes the catalytic α-subunit of a non-gastric H+/K+-ATPase that functions as a proton pump in epithelial tissues 1. The protein mediates active transport of protons outward in exchange for potassium ions across the apical membrane of airway, kidney, and colon epithelial cells, utilizing ATP hydrolysis as an energy source 2345. In airways, ATP12A plays a critical role in mucus acidification and regulates mucus viscosity and clearance properties 6. ATP12A dysfunction contributes to several respiratory and gastrointestinal pathologies. In cystic fibrosis, loss of bicarbonate secretion by CFTR allows unchecked ATP12A-mediated proton secretion, excessively acidifying airway surface liquid and impairing mucociliary clearance and host defense 78. ATP12A is upregulated in CF airways through bacterial infection and Type 2 inflammation signals 86, and ATP12A inhibition reverses these defects 7. ATP12A overexpression in idiopathic pulmonary fibrosis contributes to disease progression, with ATP12A inhibition via vonoprazan preventing bleomycin-induced fibrosis in mice 9. Additionally, altered ATP12A localization and expression patterns occur in prostate cancer and colorectal toxicity responses 1011. These findings establish ATP12A as an emerging therapeutic target for respiratory and gastrointestinal diseases.