Background: Mazdutide (IBI362) is a novel dual agonist targeting both glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR). Previous studies showed that Mazdutide significantly reduces serum uric acid levels in hyperuricemic rats. However, the underlying mechanisms remain unclear. This study explores hepatic metabolic and transcriptional changes induced by Mazdutide in a hyperuricemic rat model to better understand its urate-lowering effects.
Methods: Hyperuricemia was induced in rats by a high-fat diet combined with adenine and potassium oxonate administration. After 18 days of Mazdutide treatment, food and water intake, body weight, serum uric acid, and renal function markers were assessed. Hepatic oxidative stress was evaluated, and targeted LC-MS metabolomics was performed to analyze metabolic alterations. Single-nucleus RNA sequencing (snRNA-seq) examined transcriptional changes in hepatocyte subpopulations.
In vitro, human hepatocyte THLE-2 cells were cultured under hyperuricemic conditions and treated with Mazdutide, Semaglutide, or Allopurinol. Intracellular and extracellular uric acid levels were measured. GCGR expression was knocked down by siRNA in THLE-2 cells to evaluate the receptor dependency of Mazdutide's effects.
Results: Mazdutide significantly reduced body weight, food and water intake, and lowered serum uric acid, creatinine, and blood urea nitrogen levels, without affecting uric acid excretion via kidneys or intestines. Semaglutide showed no significant urate-lowering effect under the same conditions.
Targeted metabolomics revealed suppression of purine precursors—including xanthosine and adenosine—and glycolytic intermediates such as glucose-6-phosphate, D-(+)-glucose, L-alanine, and lactic acid. Concurrently, fatty acid–related metabolites increased, indicating a metabolic shift toward enhanced lipid utilization and reduced purine synthesis. Mazdutide also markedly increased hepatic antioxidant enzyme activities (SOD, GSH, CAT) and decreased oxidative stress markers (ROS, MDA), suggesting improved hepatic oxidative status.
SnRNA-seq showed reversal of downregulated fatty acid oxidation genes and downregulation of genes involved in fatty acid synthesis, glucose metabolism, and purine biosynthesis after treatment, reflecting metabolic reprogramming favoring reduced purine generation.
In vitro, Mazdutide significantly reduced intracellular and extracellular uric acid levels in hepatocytes under hyperuricemic conditions, whereas Semaglutide had no significant effect. This urate-lowering effect of Mazdutide was abolished following GCGR knockdown, confirming its GCGR dependency. 
Conclusions: Mazdutide effectively lowers serum uric acid by reprogramming hepatic metabolism toward enhanced lipid utilization, reduced purine synthesis, and improved oxidative stress through GCGR-dependent mechanisms. Unlike Semaglutide, Mazdutide exhibits robust urate-lowering activity both in vivo and in vitro, highlighting its therapeutic potential for hyperuricemia and related metabolic disorders.These findings suggest that Mazdutide may offer therapeutic benefits for patients with hyperuricemia, particularly those with obesity-related metabolic disorders.

Category:
Track 1: Metabolism and Integrative Physiology