You Xiaoe, Guo Baochun, Wang Zhen, Ma Hualin, Liu Lixia, Zhou Ru, Zheng Yaxuan, Zhang Xinzhou
The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China.
Department of Nephrology, Shenzhen Peoples Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China.
Mol Omics. 2023 Jul 10;19(6):473-483. doi: 10.1039/d3mo00015j.
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.
罗沙司他（FG-4592）是一种缺氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHI），用于治疗与慢性肾脏病相关的低血红蛋白患者。由于各种HIF介导的适应性反应，FG-4592在针对各种疾病的治疗应用中引起了极大关注。然而，由于对其潜在机制缺乏了解，罗沙司他的临床应用仍然有限。在此，我们采用无标记定量液相色谱-串联质谱（LC-MS-MS）蛋白质组学和非靶向代谢组学方法，研究肾性贫血患者在罗沙司他治疗前后尿液中的蛋白质和代谢物变化。结果通过平行反应监测（PRM）进行验证。在从肾性贫血患者获得的尿液样本中，罗沙司他治疗后共有46种蛋白质（包括15种上调蛋白和31种下调蛋白）和207种代谢物发生了显著变化。然后，通过PRM对改变的蛋白质进行进一步验证。最后，蛋白质组学与代谢组学分析表明，Ras信号通路、半胱氨酸和甲硫氨酸代谢、精氨酸和脯氨酸代谢以及胆固醇代谢是罗沙司他治疗后改变的主要通路。多组学分析表明，罗沙司他可以改变蛋白质表达并逆转潜在的代谢变化，从而在临床实践中发挥降压、脂质代谢调节和肾脏保护作用。
