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Integrated proteomic and metabolomic profiling of urine of renal anemia patients uncovers the molecular mechanisms of roxadustat

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MOLECULAR OMICS
卷 19, 期 6, 页码 473-483

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ROYAL SOC CHEMISTRY
DOI: 10.1039/d3mo00015j

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This study used label-free quantitative LC-MS-MS proteomics and un-targeted metabolomics to investigate the protein and metabolite changes in the urine of renal anemia patients before and after Roxadustat therapy. Results showed that Roxadustat treatment significantly altered 46 proteins (including 15 upregulated and 31 downregulated proteins) and 207 metabolites in urine samples. The altered proteins were validated by PRM. Proteomics and metabolomics analysis revealed that Roxadustat could modulate protein expression and reverse potential metabolic changes, exerting hypotensive, lipid metabolic regulation, and renoprotective effects in clinical practice.
Roxadustat (FG-4592) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) prescribed to patients with low hemoglobin associated with chronic kidney disease. Due to the various HIF-mediated adaptive responses, FG-4592 has attracted significant interest for therapeutic use against various diseases. However, the clinical application of Roxadustat remains limited due to a lack of understanding of its underlying mechanisms. Herein, we performed label-free quantitative liquid chromatography with tandem mass spectrometry (LC-MS-MS) proteomics and un-targeted metabolomics to study the protein and metabolite alterations in the urine of renal anemia patients before and after Roxadustat therapy. The results were validated by parallel reaction monitoring (PRM). A total of 46 proteins (including 15 upregulated and 31 downregulated proteins) and 207 metabolites were significantly altered after Roxadustat treatment in urine samples obtained from renal anemia patients. Then, the altered proteins were further validated by PRM. Finally, proteomics combined with metabolomics analysis revealed that the Ras signalling pathway, cysteine and methionine metabolism, arginine and proline metabolism, and cholesterol metabolism were the main pathways altered by Roxadustat treatment. The multi-omics analysis revealed that Roxadustat could alter the protein expression and reverse the potential metabolic changes to exert hypotensive, lipid metabolic regulation, and renoprotective effects in clinical practice.

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