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Ethnopharmacological relevance: Shizhifang Decoction, a traditional Chinese medicine prescription formulated by Professor Zheng Pingdong of Shuguang Hospital, has been widely utilized in clinical settings for the treatment of hyperuricemia due to its proven safety and efficacy. Objective: In this study, we used network pharmacology, molecular docking technology, and experimental validation to elucidate the therapeutic effects and underlying mechanisms of Shizhifang Decoction in managing hyperuricemia. Methods: Quality control and component identification of the freeze-dried powder of Shizhifang Decoction were conducted using ultra-high performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry. Active ingredients and their corresponding targets were obtained from Traditional Chinese Medicine Systems Pharmacology, Traditional Chinese Medicine Information Database, The Encyclopedia of Traditional Chinese Medicine, and other databases. Disease-related targets for hyperuricemia were collected from GeneCards and DisGeNET databases. The Venny platform is used to screen common targets for drug active ingredients and diseases. Subsequently, we constructed an active component-target-disease interaction network using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, create a component disease common target network using Cytoscape 3.9.1 software, from which core targets were selected. Import common targets into the Database for Annotation, Visualization and Integrated Discovery (DAVID) for Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Molecular docking was then conducted to validate the binding capacity of key active ingredients and their associated targets in Shizhifang Decoction. The theoretical predictions were further confirmed through in vitro and in vivo experiments. Result: A total of 35 active ingredients and 597 action targets were identified, resulting in 890 disease-related targets for hyperuricemia. After comprehensive analysis, 99 common targets were determined. Protein-protein interaction network analysis revealed crucial relationships between these targets and hyperuricemia. Among them, 12 core targets (CASP3, IL1B, IL6, TNF, TP53, GAPDH, PTGS2, MYC, INS, VEGFA, ESR1, PPARG) were identified. Gene Ontology enrichment analysis demonstrated significant associations with the regulation of inflammatory response, cell apoptosis, and the positive regulation of extracellular regulated protein kinases 1 and extracellular regulated protein kinases 2 cascades. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted inflammation and apoptosis-related pathways as critical mediators of Shizhifang Decoction's effects on hyperuricemia. Molecular docking studies further supported the interactions between apoptosis-related proteins and active ingredients in the extracellular regulated protein kinases 1/2 signaling pathway. In vitro experiments confirmed the downregulation of apoptosis-related proteins (caspase-3, Bax, Bcl-2) and the inhibition of the extracellular regulated protein kinases 1/2 signaling pathway by Shizhifang Decoction. These findings were also validated in animal models, demonstrating the potential of Shizhifang Decoction to mitigate renal injury induced by hyperuricemia through extracellular regulated protein kinases 1/2-mediated inhibition of renal tubular epithelial cell apoptosis. Conclusion: Our study provides valuable insights into the main mechanism by which Shizhifang Decoction ameliorates hyperuricemia. By targeting the ERK1/2 signaling pathway and modulating cell apoptosis, Shizhifang Decoction exhibits promising therapeutic potential for the treatment of hyperuricemia. These findings support the continued exploration and development of Shizhifang Decoction as a potential herbal remedy for hyperuricemia management.

Background: Hyperuricemic nephropathy is a highly prevalent kidney disease induced by excessive accumulation and deposition of monosodium urate in kidney, which contributes to the loss of kidney function. The Jiangniaosuan formulation (JNSF) is a Chinese herbal medicine treatment. The aim of this study is to evaluate its efficacy and safety among patients with hyperuricemic nephropathy at chronic kidney disease (CKD) stages 3–4 and with obstruction of phlegm turbidity and blood stasis syndrome. Methods: Our research is designed as a single-centre, double-blinded, randomized, placebo-controlled trial for 118 patients diagnosed with hyperuricemic nephropathy at CKD stages 3–4 and with obstruction of phlegm turbidity and blood stasis syndrome in mainland China. Patients are to be randomized into two groups: either the intervention group which receives JNSF 20.4 g/day combined with febuxostat 20–40 mg/day, or the control group which receives JNSF placebo 20.4 g/day combined with febuxostat 20–40 mg/day. The intervention will be carried on for 24 weeks. The change in estimated glomerular filtration rate (eGFR) is set as the primary outcome. Secondary outcomes include changes in serum uric acid, serum nitric oxide, urinary albumin/creatinine ratio, urinary N-acetyl-β-D glucosaminidase, urinary β2 microglobulin, urinary retinol binding protein and TCM syndromes in 24 weeks. Statistical analysis will be formulated by SPSS 24.0. Discussion: The trial will conduce to the comprehensive assessment in the efficacy and safety of JNSF among patients diagnosed with hyperuricemic nephropathy at CKD stages 3–4, and provide a clinical method available on systems of the combination of modern medicine and TCM.