Therapeutic Strategies for Hyperuricemia: From Small-Molecule Inhibitors to RNA Therapeutics

Hyperuricemia is a common metabolic disorder caused by purine metabolism dysregulation or impaired uric acid excretion, and it is closely associated with gout, chronic kidney disease, and cardiovascular diseases. Conventional treatments mainly rely on small-molecule drugs, such as xanthine oxidase inhibitors (e.g., allopurinol and febuxostat) and uricosuric agents (e.g., URAT1 inhibitors). However, these therapies still have limitations, including variable efficacy, poor long-term medication adherence, and potential adverse effects. With the advancement of RNA therapeutics, RNA-based strategies provide new directions for the precision management of hyperuricemia. Among them, small interfering RNA (siRNA) can suppress uric acid production or reduce renal tubular reabsorption by silencing genes encoding key metabolic enzymes or transporters (such as XOR/XDH or URAT1). In multiple animal models, this approach has demonstrated significant urate-lowering effects and renal protective benefits. Meanwhile, lipid nanoparticle (LNP)-delivered mRNA therapy restores the missing uric acid metabolic pathway in humans by re-expressing uricase in the liver. In animal models, this strategy can sustainably reduce serum uric acid levels and has shown favorable safety profiles. Therefore, the evolution from small-molecule inhibitors to RNA-based therapeutics not only expands the therapeutic targets for hyperuricemia but also promotes the development of personalized and precision medicine. In the future, with continuous improvements in delivery systems and RNA stability, RNA therapeutics are expected to become an important strategy for the long-term management of hyperuricemia.