ENT3: A lysosomal urate transporter regulating urate disposition and macrophage inflammation

Urate is the final oxidation product of purine metabolism in humans, and its extracellular accumulation leads to the formation of monosodium urate (MSU) crystals that trigger gout. Although several plasma membrane transporters involved in urate reabsorption and excretion have been identified, the mechanisms governing intracellular urate clearance remain unclear. Here, we show that equilibrative nucleoside transporter 3 (ENT3/SLC29A3) functions as a proton-coupled urate exporter from lysosomes. Using a recombinant ENT3 that localizes to the plasma membrane, we determined its urate transport kinetics (<i>K</i> _m ≈ 1.15 mM), establishing ENT3 as a low-affinity, high-capacity urate transporter. In differentiated THP-1 macrophage-like cells, ENT3 knockdown impaired clearance of phagocytosed MSU, while reducing interleukin-1β secretion likely due to diminished adenosine-mediated inflammatory signaling. These findings reveal an unrecognized role of ENT3 in lysosomal urate handling and inflammation, suggesting that ENT3 dysfunction may contribute to gout and other urate-associated disorders.