Integrating Network Pharmacology and Metabolomics to Explore the Potential Mechanism of β-Sitosterol Against Hyperuricemia Nephropathy

Background: Renal involvement resulting from hyperuricemia, known as hyperuricemia nephropathy (HN), is characterized by chronic tubulointerstitial inflammation caused by extensive urate crystal deposition. Managing this condition requires straightforward preventive or therapeutic interventions, primarily through dietary measures.Methods: In this study, the mouse model of HN was established using yeast extract combined with potassium oxonate. The effect and potential mechanism of beta-sitosterol in treating HN were investigated through biochemical indexes, pathological changes, untargeted metabolomics, and network pharmacology.Results: beta-Sitosterol reduced the levels of four biomarkers of HN: uric acid (UA), creatinine (CRE), blood urea nitrogen (BUN), and xanthine oxidase (XOD). It also mitigated inflammatory injury in renal tissues and reversed the abnormal expression of four key urate transporter proteins: glucose transporter protein 9 (GLUT9), organic anion transporter 1 (OAT1), ATP-binding cassette transporter G2 (ABCG2), and urate transporter 1 (URAT1). To explore the mechanism of beta-sitosterol in treating HN, this study employed network pharmacology and metabolomics to analyze 27 intersecting gene targets and 14 differential metabolites. The findings indicated that glutathione (GSH) metabolism might be a crucial pathway. Treatment with beta-sitosterol increased the levels of reduced GSH as well as the activity and expression of 6-phosphogluconate dehydrogenase (G6PDH) in mice, thereby effectively modulating GSH metabolism. This study proposes a novel strategy using beta-sitosterol for treating HN, providing a promising approach for addressing this condition.