Advancements in therapeutic targets and drug development for hyperuricemia: Mechanisms, progress, and challenges

Hyperuricemia (HUA), characterized by elevated serum uric acid levels, is associated with various comorbidities such as gout, metabolic syndrome, cardiovascular diseases, renal disorders and diabetes, significantly compromising patients' quality of life. The global prevalence of hyperuricemia has increased, with a growing burden reported among younger populations, highlighting the need for effective management strategies. However, current urate-lowering therapies remain limited in variety and efficacy. Long-term urate-lowering therapy is indicated for symptomatic primary hyperuricemia (e.g., gout, tophi, or uric acid nephrolithiasis), whereas its use in asymptomatic cases remains controversial, with recommendations varying across guidelines, particularly for high-risk individuals. Even for patients who meet the treatment criteria, available drugs often prove inadequate, particularly in refractory cases, revealing a critical gap in safe and effective treatment options. To address this challenge, this review narratively outlines the key targets in urate-lowering therapy, including xanthine oxidase for uric acid production, the renal reabsorption transporter URAT1, and serum uric acid regulation, along with their underlying mechanisms. It also summarizes recent advances in urate-lowering agents and compares their pharmacokinetic and pharmacodynamic profiles. Beyond conventional pharmacological treatments, this review discusses emerging therapeutic strategies, including probiotic-based interventions, small interfering RNA -based therapies, and natural products. Furthermore, recent genetic studies and multi-omics analyses have identified potential therapeutic genes that merit further investigation and could inform the development of future treatments. By synthesizing findings from international research, this review aims to lay the groundwork for the development of innovative therapeutic approaches and advanced pharmacological strategies for hyperuricemia.