URAT1 inhibition in hyperuricemia and gout: from transporter biology to clinical precision therapy.

Impaired renal urate excretion is a major mechanism underlying hyperuricemia and gout, with urate transporter 1 (URAT1), encoded by SLC22A12, playing a central role in proximal tubular urate reabsorption. This review summarizes the biological relevance of URAT1, the pharmacological evolution of URAT1 inhibitors, and their clinical implications in urate-lowering therapy. Evidence from transporter biology, structural pharmacology, pharmacokinetic and pharmacodynamic studies, and clinical trials was narratively synthesized. URAT1 inhibitors lower serum urate by blocking renal tubular urate reabsorption and increasing urinary urate excretion, providing a mechanism complementary to xanthine oxidase inhibition. Early uricosuric agents established the clinical value of this approach but are limited by non-selective transporter inhibition, tolerability concerns, drug-drug interactions, and organ-specific safety issues. Newer selective URAT1 inhibitors have been developed to improve transporter selectivity, pharmacodynamic precision, and clinical usability. Current evidence supports selective URAT1 inhibition as an effective strategy for achieving serum urate targets, particularly in underexcretion-type hyperuricemia, while renal monitoring and prevention of uric acid stone formation remain important. Emerging agents may further expand treatment options, but long-term renal, hepatic, and cardiovascular safety require further validation. Overall, URAT1 inhibition represents a rational and increasingly precise therapeutic strategy for hyperuricemia and gout, with future research needed to define its long-term outcomes, comparative effectiveness, pharmacogenomic predictors, and broader cardio-renal-metabolic implications.