{"title":"Nobiletin from Xiaoyu Xiezhuo Decoction: Restoring Mitochondrial Dynamics and Alleviating Renal Ischemia-Reperfusion Injury via M1 Macrophage Modulation.","authors":"Yuan Yuan, Jing Huang, Yinchao Zhou, Zhibo Weng, Yiru Weng, Zhouzhou Dong","doi":"10.1159/000551502","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>There have been reports that the traditional Chinese medicine formula Xiaoyu Xiezhuo Decoction (XYXZD) protects against kidney injury. Its possible mechanisms in renal ischemia-reperfusion injury (IRI) remain unclear, though. Investigating XYXZD's function and possible therapeutic effects on renal IRI is the goal of this investigation.</p><p><strong>Methods: </strong>Liquid chromatography-mass spectrometry and network pharmacology were applied to identify key target genes associated with XYXZD and renal IRI. Molecular docking was employed to forecast the binding affinity of bioactive compounds to these targets. The effects of nobiletin (NOB) on macrophage polarization, inflammatory cytokine production, mitochondrial function, and oxidative stress were evaluated. The impact of NOB on HK-2 mitochondrial dynamics through M1 macrophage polarization was evaluated via the cell counting kit-8 assay, enzyme-linked immunosorbent assay, Western blotting, and transmission electron microscopy.</p><p><strong>Results: </strong>Network pharmacology analysis identified matrix metalloproteinase-9 (MMP9) and poly(ADP-ribose) polymerase 1 (PARP1) as key regulatory factors linking macrophage polarization and mitochondrial function. Molecular docking revealed a strong binding affinity between NOB and MMP9. NOB reduced M1 macrophage polarization, along with the downregulation of pro-inflammatory cytokines interleukin-1 beta and interleukin-6. In HK-2 cells, NOB mitigated mitochondrial dysfunction by modulating M1 macrophage polarization, reducing reactive oxygen species production, and restoring mitochondrial dynamics.</p><p><strong>Conclusion: </strong>By preventing M1 macrophage polarization, lowering inflammation, and reestablishing mitochondrial homeostasis in renal tubular epithelial cells, this study showed that NOB has renoprotective benefits. These results provided fresh perspectives on NOB's potential as a treatment for renal IRI.</p>","PeriodicalId":17813,"journal":{"name":"Kidney & blood pressure research","volume":" ","pages":"285-298"},"PeriodicalIF":2.1000,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197149/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Kidney & blood pressure research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1159/000551502","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/3/17 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: There have been reports that the traditional Chinese medicine formula Xiaoyu Xiezhuo Decoction (XYXZD) protects against kidney injury. Its possible mechanisms in renal ischemia-reperfusion injury (IRI) remain unclear, though. Investigating XYXZD's function and possible therapeutic effects on renal IRI is the goal of this investigation.
Methods: Liquid chromatography-mass spectrometry and network pharmacology were applied to identify key target genes associated with XYXZD and renal IRI. Molecular docking was employed to forecast the binding affinity of bioactive compounds to these targets. The effects of nobiletin (NOB) on macrophage polarization, inflammatory cytokine production, mitochondrial function, and oxidative stress were evaluated. The impact of NOB on HK-2 mitochondrial dynamics through M1 macrophage polarization was evaluated via the cell counting kit-8 assay, enzyme-linked immunosorbent assay, Western blotting, and transmission electron microscopy.
Results: Network pharmacology analysis identified matrix metalloproteinase-9 (MMP9) and poly(ADP-ribose) polymerase 1 (PARP1) as key regulatory factors linking macrophage polarization and mitochondrial function. Molecular docking revealed a strong binding affinity between NOB and MMP9. NOB reduced M1 macrophage polarization, along with the downregulation of pro-inflammatory cytokines interleukin-1 beta and interleukin-6. In HK-2 cells, NOB mitigated mitochondrial dysfunction by modulating M1 macrophage polarization, reducing reactive oxygen species production, and restoring mitochondrial dynamics.
Conclusion: By preventing M1 macrophage polarization, lowering inflammation, and reestablishing mitochondrial homeostasis in renal tubular epithelial cells, this study showed that NOB has renoprotective benefits. These results provided fresh perspectives on NOB's potential as a treatment for renal IRI.
期刊介绍：
This journal comprises both clinical and basic studies at the interface of nephrology, hypertension and cardiovascular research. The topics to be covered include the structural organization and biochemistry of the normal and diseased kidney, the molecular biology of transporters, the physiology and pathophysiology of glomerular filtration and tubular transport, endothelial and vascular smooth muscle cell function and blood pressure control, as well as water, electrolyte and mineral metabolism. Also discussed are the (patho)physiology and (patho) biochemistry of renal hormones, the molecular biology, genetics and clinical course of renal disease and hypertension, the renal elimination, action and clinical use of drugs, as well as dialysis and transplantation. Featuring peer-reviewed original papers, editorials translating basic science into patient-oriented research and disease, in depth reviews, and regular special topic sections, ''Kidney & Blood Pressure Research'' is an important source of information for researchers in nephrology and cardiovascular medicine.
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