Tigulixostat Alleviates Hyperuricemic Nephropathy by Promoting M2 Macrophage Polarization

  • J Inflamm Res. 2025 Jan 3:18:17-30. doi: 10.2147/JIR.S500101.
Lina Xue  #  1  2 ,  Qianru Tao  #  1  2 ,  Haining Chang  #  1 ,  Shu Yan  1 ,  Lei Wang  3 ,  Zefang Zhao  4 ,  Chao Tu  1
Affiliations
  • 1. Department of Internal Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China.
  • 2. Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China.
  • 3. Nanjing jinyu medical examination laboratory, Nanjing, Jiangsu, People's Republic of China.
  • 4. Hongyi Honor College, Wuhan University, Wuhan, Hubei, People's Republic of China.
  • # Contributed equally.
PMID: 39780982 DOI: 10.2147/JIR.S500101
Abstract

Purpose: Serum uric acid (SUA) is primarily produced through the hydrolysis of purines in the liver, with its excretion largely handled by the kidneys. Urate transporter 1 (URAT1) inhibitors are known to enhance uric acid elimination via the kidneys, but they also increase the risk of kidney stone formation. Currently, Xanthine Oxidase (XO) inhibitors are the predominant uric-lowering medications on the market.

Methods: In this study, we utilized single-cell RNA Sequencing, spatial metabolomics, plasma metabolomics, flow cytometry to explore the effects of Tigulixostat on uric acid level and hyperuricemic nephropathy (HN) in Uox-KO mouse model.

Results: In this study, we discovered that Tigulixostat (LC350189) more effectively reduced SUA levels and resulted in better renal outcomes compared to allopurinol, without inducing liver injury in urate oxidase knockout (Uox-KO) mice. Mechanistically, we found that Tigulixostat improved HN by promoting M2 macrophage polarization.

Conclusion: These findings suggest Tigulixostat as a promising therapeutic option for managing hyperuricemia and related kidney conditions.

Keywords
Single-cell RNA sequencing; Uox-KO; hyperuricemic nephropathy; macrophage; tigulixostat.
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