Acidification

Acidification is a biological process characterized by the reduction of pH within specific cellular or extracellular compartments, rather than a discrete molecular target. It is mediated by an array of specialized proteins, including the gastric H+/K+-ATPase (proton pump) responsible for gastric acid secretion, vacuolar-type H+-ATPases (V-ATPases) that acidify lysosomes and endosomes, and carbonic anhydrases like CAIX that contribute to the acidic tumor microenvironment (1, 6, 11). These molecular drivers are critical therapeutic targets: proton pump inhibitors (PPIs) inhibit gastric acidification to treat acid-reflux disorders, while inhibitors of V-ATPase or CAIX are being explored to disrupt cancer progression and lysosomal dysfunction (4, 7, 13). Drugs interact with this process by blocking the active transport of protons or the enzymatic generation of bicarbonate and hydrogen ions, thereby shifting the local pH (8, 18). Because pH regulation is fundamental to cellular health, targeting acidification-related proteins involves significant safety considerations, including potential impacts on systemic ion balance and nutrient absorption (5, 16).

Other names

Gastric acidificationLysosomal acidificationTumor microenvironment acidificationProton secretionAcidosisExtracellular acidification

Drugs targeting this process primarily work by inhibiting the molecular drivers of proton flux, such as the gastric H+/K+-ATPase, vacuolar-type H+-ATPases (V-ATPases), or carbonic anhydrases, which prevents the build-up of hydrogen ions in specific compartments and shifts the local pH toward neutrality (1, 2, 7, 18).