Evaluating renal injury characteristics in different rat models of hyperuricemia and elucidating pathological molecular mechanisms via serum metabolomics

Hyperuricemia has emerged as a significant global health concern, closely associated with various metabolic disorders. The adverse effects frequently observed with current pharmacological treatments for hyperuricemia highlight the urgent need for reliable animal models to elucidate the disease's pathophysiological mechanisms, thereby facilitating the development of safer and more effective therapies. In this study, we established three rat models of hyperuricemia using potassium oxonate, either alone or in combination with fructose and adenine. Each model exhibited distinct pathological changes, with the combination of potassium oxonate, fructose, and adenine causing significantly more severe damage to liver and kidney functions than potassium oxonate alone. Serum metabolomics analyses revealed profound dysregulation in the metabolic pathways of purine, pyrimidines, and glutathione, underscoring the pivotal role of oxidative stress in the progression of hyperuricemia. We identified key biomarkers such as orotidine, ureidosuccinic acid, uracil, and pseudouridine, which are associated with uric acid-induced damage to hepatic and renal systems. MetOrigin tracing analysis further revealed that differential metabolites related to hyperuricemia are primarily involved in host-microbiome co-metabolic pathways, particularly in purine metabolism, with bacterial phyla such as <i>Pseudomonadota</i>, <i>Actinomycetota</i>, and <i>Ascomycota</i> being closely linked to the critical metabolic processes of uric acid production. These findings not only enhance our understanding of the pathogenic mechanisms underlying hyperuricemia but also provide a robust experimental model foundation for the development of innovative treatment strategies.