Exocytosed ATP as a therapeutic target for inflammatory and metabolic diseases.

Extracellular adenosine triphosphate (eATP) is a key intercellular signaling molecule in purinergic transmission and contributes to pain, inflammation, and tissue dysfunction in a wide range of diseases. Although eATP is released through membrane damage, conductive pathways, and vesicular exocytosis, the biological and pharmacological significance of ATP released by exocytosis has remained insufficiently defined. Vesicular nucleotide transporter (VNUT), encoded by SLC17A9, which loads ATP into secretory vesicles, is essential for ATP exocytosis and has enabled direct investigation of the roles of exocytosed ATP in physiology and disease. Accumulating evidence indicates that VNUT-dependent ATP exocytosis contributes to inflammatory signaling, sensory transmission, metabolic dysregulation, and cancer-related processes, while its inhibition shows therapeutic potential in experimental models of pathological states. This review summarizes recent advances in the molecular basis, regulation, pharmacological manipulation, and disease relevance of VNUT-mediated ATP exocytosis. We also discuss the therapeutic potential of targeting exocytosed ATP for pain, chronic inflammation, and metabolic disorders.