Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Scientific Reports
  • View all journals
  • Search
  • My Account Login
  • Content Explore content
  • About the journal
  • Publish with us
  • Sign up for alerts
  • RSS feed
  1. nature
  2. scientific reports
  3. articles
  4. article
Identification of key hub genes in spinal cord ischemia-reperfusion injury via integrated bioinformatics analysis and in vivo validation
Download PDF
Download PDF
  • Article
  • Open access
  • Published: 10 February 2026

Identification of key hub genes in spinal cord ischemia-reperfusion injury via integrated bioinformatics analysis and in vivo validation

  • Mingjie Gao1,2,
  • Haitong Liu3,
  • Caixia Sun3,
  • Jishan Yuan2,
  • Lei Wang2 &
  • …
  • Jinzhong Ma1,4 

Scientific Reports , Article number:  (2026) Cite this article

  • 238 Accesses

  • Metrics details

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Computational biology and bioinformatics
  • Neurology

Abstract

Spinal cord ischemia-reperfusion injury (SCII) often causes neurological damage and devastating sensory and motor dysfunction. Identifying key genes and signaling pathways in SCII progression may provide novel therapeutic targets. Two gene expression datasets (GSE138966 and GSE167274) were obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using R software, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Hub genes were screened via Venn analysis, and a protein-protein interaction (PPI) network was constructed using Cytoscape software. Key hub genes were validated by qRT-PCR in a rat SCII model. A total of 99 hub genes were identified, including 60 up-regulated and 39 down-regulated genes. KEGG analysis revealed significant enrichment in MAPK, cAMP, and Rap1 signaling pathways. PPI network analysis highlighted Ccl2, Mmp9, Itgb1, Timp1, Myd88, and Lgals3 as central nodes. qRT-PCR validation showed persistent up-regulation of Tnc, Thbs2, and S100a10 at 1 h, 24 h, and 48 h post-SCII; early up-regulation of Msn, Lcp1, Lcn2, and Akap12 at 1 h; and delayed up-regulation of Itga5 at 48 h (P < 0.05). This study identifies novel, key SCII-related genes that have been largely overlooked and, for the first time, defines their time-dependent expression patterns via in vivo experimental validation. Our findings provide crucial mechanistic insights and nominate promising therapeutic targets for SCII.

Similar content being viewed by others

Identification of key autophagy-related genes and pathways in spinal cord injury

Article Open access 19 March 2024

Integrated bioinformatics analysis identified cuproptosis-related hub gene Mpeg1 as potential biomarker in spinal cord injury

Article Open access 15 January 2025

Identification and bioinformatics analysis of genes associated with pyroptosis in spinal cord injury of rat and mouse

Article Open access 18 June 2024

Data availability

The datasets selected in our research can be found and downloaded for free online. GEO Database accession number: GSE138966, GSE167274. All data generated or analysed during this study are included in this published article and its supplementary information files.

References

  1. Sueda, T. & Takahashi, S. Spinal cord injury as a complication of thoracic endovascular aneurysm repair. Surg. Today. 48, 473–477. https://doi.org/10.1007/s00595-017-1588-5 (2018).

    Google Scholar 

  2. Kong, X. & Gao, J. Macrophage polarization: a key event in the secondary phase of acute spinal cord injury. J. Cell. Mol. Med. 21, 941–954. https://doi.org/10.1111/jcmm.13034 (2017).

    Google Scholar 

  3. Stenudd, M., Sabelstrom, H. & Frisen, J. Role of endogenous neural stem cells in spinal cord injury and repair. JAMA Neurol. 72, 235–237. https://doi.org/10.1001/jamaneurol.2014.2927 (2015).

    Google Scholar 

  4. Henmi, S. et al. Comparison of early patency rate and long-term outcomes of various techniques for reconstruction of segmental arteries during thoracoabdominal aortic aneurysm repair. Eur. J. Cardiothorac. Surg. https://doi.org/10.1093/ejcts/ezz015 (2019).

    Google Scholar 

  5. Jin, W., Botchway, B. O. A. & Liu, X. Curcumin can activate the Nrf2/HO-1 signaling pathway and scavenge free radicals in spinal cord injury treatment. Neurorehabil Neural Repair. 35, 576–584. https://doi.org/10.1177/15459683211011232 (2021).

    Google Scholar 

  6. Liu, W. Z., Ma, Z. J., Li, J. R. & Kang, X. W. Mesenchymal stem cell-derived exosomes: therapeutic opportunities and challenges for spinal cord injury. Stem Cell. Res. Ther. 12, 102. https://doi.org/10.1186/s13287-021-02153-8 (2021).

    Google Scholar 

  7. Orlov, Y. L., Anashkina, A. A., Klimontov, V. V. & Baranova, A. V. Medical Genetics, genomics and bioinformatics aid in Understanding molecular mechanisms of human diseases. Int. J. Mol. Sci. 22, 256. https://doi.org/10.3390/ijms22189962 (2021).

  8. Wang, D. et al. Bioinformatics-Based analysis of the lncRNA-miRNA-mRNA network and TF regulatory network to explore the regulation mechanism in spinal cord Ischemia/Reperfusion injury. Front. Genet. 12, 650180. https://doi.org/10.3389/fgene.2021.650180 (2021).

    Google Scholar 

  9. Zhou, Z., Han, B., Jin, H., Chen, A. & Zhu, L. Changes in long non-coding RNA transcriptomic profiles after ischemia-reperfusion injury in rat spinal cord. PeerJ 8, e8293. https://doi.org/10.7717/peerj.8293 (2020).

    Google Scholar 

  10. Pavic, G. et al. Microglia contributes to remyelination in cerebral but not spinal cord ischemia. Glia 69, 2739–2751. https://doi.org/10.1002/glia.24068 (2021).

    Google Scholar 

  11. Ritchie, M. E. et al. K. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47. https://doi.org/10.1093/nar/gkv007 (2015).

    Google Scholar 

  12. Wilkerson, M. D. & Hayes, D. N. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics 26, 1572–1573. https://doi.org/10.1093/bioinformatics/btq170 (2010).

    Google Scholar 

  13. Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30. https://doi.org/10.1093/nar/28.1.27 (2000).

    Google Scholar 

  14. Yu, G., Wang, L. G., Han, Y. & He, Q. Y. ClusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287. https://doi.org/10.1089/omi.2011.0118 (2012).

    Google Scholar 

  15. Hu, X., Ni, S., Zhao, K., Qian, J. & Duan, Y. Bioinformatics-Led discovery of osteoarthritis biomarkers and inflammatory infiltrates. Front. Immunol. 13, 871008. https://doi.org/10.3389/fimmu.2022.871008 (2022).

    Google Scholar 

  16. Szklarczyk, D. et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47, D607–D613. https://doi.org/10.1093/nar/gky1131 (2019).

    Google Scholar 

  17. Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504. https://doi.org/10.1101/gr.1239303 (2003).

    Google Scholar 

  18. Yin, F. et al. Transplantation of mesenchymal stem cells exerts anti-apoptotic effects in adult rats after spinal cord ischemia-reperfusion injury. Brain Res. 1561, 1–10. https://doi.org/10.1016/j.brainres.2014.02.047 (2014).

    Google Scholar 

  19. Basso, D. M., Beattie, M. S. & Bresnahan, J. C. Descending systems contributing to locomotor recovery after mild or moderate spinal cord injury in rats: experimental evidence and a review of literature. Restor. Neurol. Neurosci. 20, 189–218 (2002).

    Google Scholar 

  20. Yang, J. et al. An iron delivery pathway mediated by a Lipocalin. Mol. Cell. 10, 1045–1056. https://doi.org/10.1016/s1097-2765(02)00710-4 (2002).

    Google Scholar 

  21. Kuramoto, K., Liang, H., Hong, J. H. & He, C. Exercise-activated hepatic autophagy via the FN1-α5β1 integrin pathway drives metabolic benefits of exercise. Cell Metab. 35, 620–632 e625. https://doi.org/10.1016/j.cmet.2023.01.011 (2023).

  22. Gelman, I. H. Emerging roles for SSeCKS/Gravin/AKAP12 in the control of cell Proliferation, cancer Malignancy, and barriergenesis. Genes Cancer. 1, 1147–1156. https://doi.org/10.1177/1947601910392984 (2010).

    Google Scholar 

  23. Morellini, F. & Schachner, M. Enhanced novelty-induced activity, reduced anxiety, delayed resynchronization to daylight reversal and weaker muscle strength in tenascin-C-deficient mice. Eur. J. Neurosci. 23, 1255–1268. https://doi.org/10.1111/j.1460-9568.2006.04657.x (2006).

    Google Scholar 

  24. Wabnitz, G. H. et al. Costimulation induced phosphorylation of L-plastin facilitates surface transport of the T cell activation molecules CD69 and CD25. Eur. J. Immunol. 37, 649–662. https://doi.org/10.1002/eji.200636320 (2007).

    Google Scholar 

  25. Madureira, P. A., O’Connell, P. A., Surette, A. P., Miller, V. A. & Waisman, D. M. The biochemistry and regulation of S100A10: a multifunctional plasminogen receptor involved in oncogenesis. J. Biomed. Biotechnol. 2012, 353687. https://doi.org/10.1155/2012/353687 (2012).

  26. Huang, L., Wong, T. Y., Lin, R. C. & Furthmayr, H. Replacement of threonine 558, a critical site of phosphorylation of Moesin in vivo, with aspartate activates F-actin binding of Moesin. Regulation by conformational change. J. Biol. Chem. 274, 12803–12810. https://doi.org/10.1074/jbc.274.18.12803 (1999).

    Google Scholar 

  27. Serrador, J. M. et al. CD43 interacts with Moesin and Ezrin and regulates its redistribution to the uropods of T lymphocytes at the cell-cell contacts. Blood 91, 4632–4644 (1998).

    Google Scholar 

  28. Simantov, R., Febbraio, M. & Silverstein, R. L. The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein. Matrix Biol. 24, 27–34. https://doi.org/10.1016/j.matbio.2004.11.005 (2005).

    Google Scholar 

  29. Alizadeh, A., Dyck, S. M. & Karimi-Abdolrezaee, S. Traumatic spinal cord injury: an overview of Pathophysiology, models and acute injury mechanisms. Front. Neurol. 10, 282. https://doi.org/10.3389/fneur.2019.00282 (2019).

    Google Scholar 

  30. Hutson, T. H. & Di Giovanni, S. The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration. Nat. Rev. Neurol. 15, 732–745. https://doi.org/10.1038/s41582-019-0280-3 (2019).

    Google Scholar 

  31. Jiang, W. et al. CCL2 is a key regulator and therapeutic target for periodontitis. J. Clin. Periodontol. 50, 1644–1657. https://doi.org/10.1111/jcpe.13872 (2023).

    Google Scholar 

  32. Du, S. et al. X. A nerve injury-specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression. J. Clin. Invest. 132, 689. https://doi.org/10.1172/jci153563 (2022).

  33. Lee, J. Y., Kim, H. S., Choi, H. Y., Oh, T. H. & Yune, T. Y. Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury. Brain 135, 2375–2389. https://doi.org/10.1093/brain/aws171 (2012).

    Google Scholar 

  34. Rempe, R. G., Hartz, A. M. S. & Bauer, B. Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J. Cereb. Blood Flow. Metab. 36, 1481–1507. https://doi.org/10.1177/0271678x16655551 (2016).

    Google Scholar 

  35. Wang, Q. et al. Myd88 knockdown with RNA interference induces in vitro immune hyporesponsiveness in dendritic cells from rhesus monkeys. Immunogenetics 74, 303–312. https://doi.org/10.1007/s00251-022-01260-x (2022).

    Google Scholar 

  36. Bayer, A. L. & Alcaide, P. MyD88: at the heart of inflammatory signaling and cardiovascular disease. J. Mol. Cell. Cardiol. 161, 75–85. https://doi.org/10.1016/j.yjmcc.2021.08.001 (2021).

    Google Scholar 

  37. Rong, J. et al. Long non-coding RNA KCNQ1OT1/microRNA-204-5p/LGALS3 axis regulates myocardial ischemia/reperfusion injury in mice. Cell. Signal. 66, 109441. https://doi.org/10.1016/j.cellsig.2019.109441 (2020).

    Google Scholar 

  38. Yan, L. et al. Hspb1 and Lgals3 in spinal neurons are closely associated with autophagy following excitotoxicity based on machine learning algorithms. PLoS One. 19, e0303235. https://doi.org/10.1371/journal.pone.0303235 (2024).

    Google Scholar 

  39. Tavares, L. P. et al. Blame the signaling: role of cAMP for the resolution of inflammation. Pharmacol. Res. 159, 105030. https://doi.org/10.1016/j.phrs.2020.105030 (2020).

    Google Scholar 

  40. Xu, Z. et al. ERK1/2 and p38 mitogen-activated protein kinase mediate iNOS-induced spinal neuron degeneration after acute traumatic spinal cord injury. Life Sci. 79, 1895–1905. https://doi.org/10.1016/j.lfs.2006.06.023 (2006).

    Google Scholar 

  41. Sun, X. et al. Activation of the Epac/Rap1 signaling pathway alleviates blood-brain barrier disruption and brain damage following cerebral ischemia/reperfusion injury. Int. Immunopharmacol. 117, 110014. https://doi.org/10.1016/j.intimp.2023.110014 (2023).

    Google Scholar 

  42. Midwood, K. S., Chiquet, M., Tucker, R. P. & Orend, G. Tenascin-C at a glance. J. Cell. Sci. 129, 4321–4327. https://doi.org/10.1242/jcs.190546 (2016).

    Google Scholar 

  43. Midwood, K. et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat. Med. 15, 774–780. https://doi.org/10.1038/nm.1987 (2009).

    Google Scholar 

  44. Chang, Z. et al. THBS2 promotes gastric cancer progression and stemness via the Notch signaling pathway. Am. J. Cancer Res. 14, 3433–3450. https://doi.org/10.62347/uxwk4038 (2024).

    Google Scholar 

  45. Adams, J. C. & Lawler, J. The thrombospondins. Cold Spring Harb Perspect. Biol. 3, a009712. https://doi.org/10.1101/cshperspect.a009712 (2011).

    Google Scholar 

  46. Milosevic, A. et al. Cell- and region-specific expression of depression-related protein p11 (S100a10) in the brain. J. Comp. Neurol. 525, 955–975. https://doi.org/10.1002/cne.24113 (2017).

    Google Scholar 

  47. Okura, G. C., Bharadwaj, A. G. & Waisman, D. M. Recent advances in molecular and cellular functions of S100A10. Biomolecules 13, 569. https://doi.org/10.3390/biom13101450 (2023).

  48. Satooka, H., Nagakubo, D., Sato, T. & Hirata, T. The ERM protein Moesin regulates CD8(+) regulatory T cell homeostasis and Self-Tolerance. J. Immunol. 199, 3418–3426. https://doi.org/10.4049/jimmunol.1700074 (2017).

    Google Scholar 

  49. Wang, Y. et al. LCP1 knockdown in monocyte-derived macrophages: mitigating ischemic brain injury and shaping immune cell signaling and metabolism. Theranostics 14, 159–175. https://doi.org/10.7150/thno.88678 (2024).

    Google Scholar 

  50. Liu, R. et al. NOX activation in reactive astrocytes regulates astrocytic LCN2 expression and neurodegeneration. Cell. Death Dis. 13, 371. https://doi.org/10.1038/s41419-022-04831-8 (2022).

    Google Scholar 

  51. Wang, G. et al. Lipocalin-2 released in response to cerebral ischaemia mediates reperfusion injury in mice. J. Cell. Mol. Med. 19, 1637–1645. https://doi.org/10.1111/jcmm.12538 (2015).

    Google Scholar 

  52. Cha, J. H. et al. W. AKAP12 mediates barrier functions of fibrotic scars during CNS repair. PLoS One. 9, e94695. https://doi.org/10.1371/journal.pone.0094695 (2014).

    Google Scholar 

  53. Chen, W. et al. Migrasome-related ITGA5 for predicting prognosis, immune infiltration and drug sensitivity of hepatocellular carcinoma. Apoptosis https://doi.org/10.1007/s10495-025-02103-2 (2025).

    Google Scholar 

Download references

Acknowledgements

This study was supported by Zhenjiang Science and Technology Plan Project-Social Development (Grant No. SH2023061), the Research Fund of the First People’s Hospital of Zhenjiang (Grant No. Y2020012) and the Third Phase of “Jinshan Doctors” - Young Talents in Medical Field of Zhenjiang City.

Author information

Authors and Affiliations

  1. Department of Orthopedics, Shanghai General Hospital of Nanjing Medical University, Shanghai, 201600, China

    Mingjie Gao & Jinzhong Ma

  2. Department of Orthopedics, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China

    Mingjie Gao, Jishan Yuan & Lei Wang

  3. Department of Anesthesiology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China

    Haitong Liu & Caixia Sun

  4. Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China

    Jinzhong Ma

Authors
  1. Mingjie Gao
    View author publications

    Search author on:PubMed Google Scholar

  2. Haitong Liu
    View author publications

    Search author on:PubMed Google Scholar

  3. Caixia Sun
    View author publications

    Search author on:PubMed Google Scholar

  4. Jishan Yuan
    View author publications

    Search author on:PubMed Google Scholar

  5. Lei Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Jinzhong Ma
    View author publications

    Search author on:PubMed Google Scholar

Contributions

G.M. contributed to the study design, analysis, and interpretation of data and drafted the manuscript. L.H. and M.J. contributed to the study design and interpretation of the data, revised the manuscript and approved the final version. S.C. , W.L. and Y.J. critically revised the manuscript and approved the final manuscript. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Haitong Liu or Jinzhong Ma.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1

Supplementary Material 2

Supplementary Material 3

Supplementary Material 4

Supplementary Material 5

Supplementary Material 6

Supplementary Material 7

Supplementary Material 8

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, M., Liu, H., Sun, C. et al. Identification of key hub genes in spinal cord ischemia-reperfusion injury via integrated bioinformatics analysis and in vivo validation. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39101-6

Download citation

  • Received: 21 June 2025

  • Accepted: 03 February 2026

  • Published: 10 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-39101-6

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Download PDF

Advertisement

Explore content

  • Research articles
  • News & Comment
  • Collections
  • Subjects
  • Follow us on Facebook
  • Follow us on X
  • Sign up for alerts
  • RSS feed

About the journal

  • About Scientific Reports
  • Contact
  • Journal policies
  • Guide to referees
  • Calls for Papers
  • Editor's Choice
  • Journal highlights
  • Open Access Fees and Funding

Publish with us

  • For authors
  • Language editing services
  • Open access funding
  • Submit manuscript

Search

Advanced search

Quick links

  • Explore articles by subject
  • Find a job
  • Guide to authors
  • Editorial policies

Scientific Reports (Sci Rep)

ISSN 2045-2322 (online)

nature.com sitemap

About Nature Portfolio

  • About us
  • Press releases
  • Press office
  • Contact us

Discover content

  • Journals A-Z
  • Articles by subject
  • protocols.io
  • Nature Index

Publishing policies

  • Nature portfolio policies
  • Open access

Author & Researcher services

  • Reprints & permissions
  • Research data
  • Language editing
  • Scientific editing
  • Nature Masterclasses
  • Research Solutions

Libraries & institutions

  • Librarian service & tools
  • Librarian portal
  • Open research
  • Recommend to library

Advertising & partnerships

  • Advertising
  • Partnerships & Services
  • Media kits
  • Branded content

Professional development

  • Nature Awards
  • Nature Careers
  • Nature Conferences

Regional websites

  • Nature Africa
  • Nature China
  • Nature India
  • Nature Japan
  • Nature Middle East
  • Privacy Policy
  • Use of cookies
  • Legal notice
  • Accessibility statement
  • Terms & Conditions
  • Your US state privacy rights
Springer Nature

© 2026 Springer Nature Limited

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing