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An integrative clinical and bioinformatic analysis identifies MicroRNAs as biomarkers of ischemic stroke severity
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  • Published: 26 January 2026

An integrative clinical and bioinformatic analysis identifies MicroRNAs as biomarkers of ischemic stroke severity

  • Ceren Eyileten  ORCID: orcid.org/0000-0002-3324-96251,2,
  • Zofia Wicik1,3,
  • Andleeb Shahzadi4,
  • Sara Ahmadova1,
  • Pamela Czajka1,5,
  • Izabela Domitrz6,
  • Agata Wierzchowska-Ciok6,
  • Dagmara Mirowska-Guzel1,
  • Anna Czlonkowska1,7 &
  • …
  • Marek Postula1 

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

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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

  • Biomarkers
  • Epigenomics

Abstract

Identifying reliable circulating biomarkers is crucial for improving the diagnosis and risk stratification of patients with ischemic stroke. In this study, we evaluated several whole-blood circulating miRNAs (miR-106b-5p, miR-16-5p, miR-15b-5p, let-7e-5p, and miR-125a-3p/-5p) to determine their diagnostic and disease severity in acute ischemic stroke (AIS). Sixty AIS patients and thirty age- and sex-matched controls were included. Whole-blood miRNAs were quantified at admission and on day 7. Statistical analyses included ROC curves, multivariate logistic regression, and SHAP-based machine learning. Bioinformatic analyses assessed predicted miRNA targets, pathway enrichment, and interaction networks. MiR-125a-3p was significantly reduced in AIS at both time points, while miR-125a-5p was elevated at admission and decreased by day 7. Both miRNAs showed moderate diagnostic value (AUC 0.675 and 0.712, respectively). Higher admission levels of miR-16-5p were strongly associated with greater neurological deficit (NIHSS) and unfavorable outcome (mRS ≥ 3). Multivariate analyses confirmed high miR-16-5p and elevated CRP as independent predictors of poor outcome. Bioinformatic analyses revealed that miR-16-5p targets were enriched in pathways relevant to ischemic injury, including hypoxia response, platelet activation, coagulation, TGF-β and BDNF signaling. A target-interaction network highlighted IL6, FN1, TGFB1, ICAM1, and TLR4 as central nodes linking miR-16-5p to ischemia-inflammatory mechanisms in AIS. Circulating miRNAs display distinct expression patterns in the acute phase of AIS. miR-16-5p emerges as a promising biomarker associated with stroke severity and unfavorable outcome, while miR-125a-3p and miR-125a-5p show potential diagnostic utility. These findings strengthen mechanistic links between platelet-derived miRNAs and ischemic stroke biology. Larger, longitudinal studies integrating functional validation are warranted to confirm their clinical value.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Powers, W. J. et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 50, e344–e418 (2019).

    Google Scholar 

  2. Herpich, F. & Rincon, F. Management of acute ischemic stroke. Crit. Care Med. 48, 1654–1663 (2020).

    Google Scholar 

  3. El-Koussy, M., Schroth, G., Brekenfeld, C. & Arnold, M. Imaging of acute ischemic stroke. Eur. Neurol. 72, 309–316 (2014).

    Google Scholar 

  4. Kamtchum-Tatuene, J. & Jickling, G. C. Blood biomarkers for stroke diagnosis and management. Neuromol. Med. 21, 344–368 (2019).

    Google Scholar 

  5. Wang, S.-W., Liu, Z. & Shi, Z.-S. Non-coding RNA in acute ischemic stroke: Mechanisms, biomarkers and therapeutic targets. Cell Transpl. 27, 1763–1777 (2018).

    Google Scholar 

  6. Bartel, D. P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Google Scholar 

  7. Ma, H. et al. MicroRNAs in oral lichen planus and potential miRNA–mRNA pathogenesis with essential cytokines: A review.. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 122, 164–173 (2016).

    Google Scholar 

  8. Eyileten, C. et al. MicroRNAs as diagnostic and prognostic biomarkers in ischemic stroke-a comprehensive review and bioinformatic analysis. Cells 7, 249 (2018).

    Google Scholar 

  9. Ge, Q. et al. miRNA in plasma exosome is stable under different storage conditions. Molecules 19, 1568–1575 (2014).

    Google Scholar 

  10. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Google Scholar 

  11. Cun, Y. et al. Exosome in crosstalk between inflammation and angiogenesis: A potential therapeutic strategy for stroke. Mediat. Inflamm. 2022, 7006281 (2022).

    Google Scholar 

  12. Sabour, S. The diagnostic value of serum miRNA-221-3p, miRNA-382-5p, and miRNA-4271 in ischemic stroke: Methodological issue to avoid misinterpretation. J. Stroke Cerebrovasc. Dis. 26(5), 1161 (2017).

    Google Scholar 

  13. Chen, Y. et al. Increased circulating exosomal miRNA-223 Is associated with acute ischemic stroke. Front. Neurol. 8, 57 (2017).

    Google Scholar 

  14. Aili, Y. et al. The role of exosomal miRNAs in glioma: Biological function and clinical application. Front. Oncol. 11, 686369 (2021).

    Google Scholar 

  15. Wicik, Z. et al. The role of miRNAs in regulation of platelet activity and related diseases - A bioinformatic analysis. Platelets 33(7), 1052–1064. https://doi.org/10.1080/09537104.2022.2042233 (2022).

    Google Scholar 

  16. Czajka, P. et al. MicroRNA as potential biomarkers of platelet function on antiplatelet therapy: A review. Front. Physiol. 12, 652579 (2021).

    Google Scholar 

  17. Huang, S. et al. Identification of Blood Let-7e-5p as a biomarker for ischemic stroke. PLoS ONE 11, e0163951 (2016).

    Google Scholar 

  18. Tiedt, S. et al. RNA-Seq identifies circulating miR-125a-5p, miR-125b-5p, and miR-143-3p as potential biomarkers for acute ischemic stroke. Circ. Res. 121, 970–980 (2017).

    Google Scholar 

  19. Force, W. T. Recommendations on stroke prevention, diagnosis, and therapy report of the WHO task force on stroke and other cerebrovascular disorders. Stroke 20, 1407–1431 (1989).

    Google Scholar 

  20. Adams, H. P. Jr. et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment. Stroke 24, 35–41 (1993).

    Google Scholar 

  21. De Rosa, S. et al. Transcoronary concentration gradients of circulating microRNAs in heart failure. Eur. J. Heart Fail. 20, 1000–1010 (2018).

    Google Scholar 

  22. De Rosa, R. et al. Transcoronary concentration gradient of microRNA-133a and outcome in patients with coronary artery disease. Am. J. Cardiol. 120, 15–24 (2017).

    Google Scholar 

  23. Eyileten, C. et al. Alterations in circulating MicroRNAs and the relation of MicroRNAs to maximal oxygen consumption and intima-media thickness in ultra-marathon runners. Int. J. Environ. Res. Public Health 18, 7234 (2021).

    Google Scholar 

  24. Drost, H.-G. & Paszkowski, J. Biomartr: Genomic data retrieval with R. Bioinformatics 33, 1216–1217 (2017).

    Google Scholar 

  25. Piñero, J. et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 48, D845–D855 (2019).

    Google Scholar 

  26. Ru, Y. et al. The multiMiR R package and database: Integration of microRNA–target interactions along with their disease and drug associations. Nucleic Acids Res. 42, e133 (2014).

    Google Scholar 

  27. Zofia. .Vignette_wizbionet.Md at Master · Wizbionet/wizbionet. (Github).

  28. Wicik, Z. et al. The crosstalk between bone metabolism, lncRNAs, microRNAs and mRNAs in coronary artery calcification. Genomics 113, 503 (2021).

    Google Scholar 

  29. Doncheva, N. T., Morris, J. H., Gorodkin, J. & Jensen, L. J. Cytoscape StringApp: Network analysis and visualization of proteomics data. J. Proteome Res. 18, 623–632 (2019).

    Google Scholar 

  30. Shannon, P. et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).

    Google Scholar 

  31. Wu, J., Du, K. & Lu, X. Elevated expressions of serum miR-15a, miR-16, and miR-17-5p are associated with acute ischemic stroke. Int. J. Clin. Exp. Med. 8, 21071–21079 (2015).

    Google Scholar 

  32. Tian, C. et al. Plasma MicroRNA-16 is a biomarker for diagnosis, stratification, and prognosis of hyperacute cerebral infarction. PLoS ONE 11, e0166688 (2016).

    Google Scholar 

  33. Yang, X. et al. MicroRNA-15a/16-1 antagomir ameliorates ischemic brain injury in experimental stroke. Stroke 48, 1941–1947 (2017).

    Google Scholar 

  34. Leung, L. Y. et al. Comparison of miR-124-3p and miR-16 for early diagnosis of hemorrhagic and ischemic stroke. Clin. Chim. Acta 433, 139–144 (2014).

    Google Scholar 

  35. Huang, R. et al. Overexpressing circ_0000831 is sufficient to inhibit neuroinflammation and vertigo in cerebral ischemia through a miR-16-5p-dependent mechanism. Exp. Neurol. 353, 114047 (2022).

    Google Scholar 

  36. Li, Q. et al. Luteoloside attenuates neuroinflammation in focal cerebral ischemia in rats via regulation of the PPARγ/Nrf2/NF-κB signaling pathway. Int. Immunopharmacol. 66, 309–316 (2019).

    Google Scholar 

  37. Chaudhuri, A. D. et al. TNFα and IL-1β modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons. Cell Death Dis. 9, 363 (2018).

    Google Scholar 

  38. Riccio, A., Ahn, S., Davenport, C. M., Blendy, J. A. & Ginty, D. D. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 286, 2358–2361 (1999).

    Google Scholar 

  39. Joilin, G. et al. Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis. Brain Commun. 2, fcaa053 (2020).

    Google Scholar 

  40. Sandau, U. S. et al. Differential effects of APOE genotype on MicroRNA cargo of cerebrospinal fluid extracellular vesicles in females with Alzheimer’s disease compared to males. Front. Cell Dev. Biol. 10, 864022 (2022).

    Google Scholar 

  41. Norsworthy, P. J. et al. A blood miRNA signature associates with sporadic Creutzfeldt-Jakob disease diagnosis. Nat. Commun. 11, 3960 (2020).

    Google Scholar 

  42. Dewdney, B. et al. Circulating MicroRNAs as biomarkers for acute ischemic stroke: A systematic review. J. Stroke Cerebrovasc. Dis. 27, 522–530 (2018).

    Google Scholar 

  43. Li, P. et al. An Antagomir to MicroRNA-106b-5p ameliorates cerebral ischemia and reperfusion injury in rats via inhibiting apoptosis and oxidative stress. Mol. Neurobiol. 54, 2901–2921 (2017).

    Google Scholar 

  44. Reijerkerk, A. et al. MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: Implications for multiple sclerosis. J. Neurosci. 33, 6857–6863 (2013).

    Google Scholar 

  45. Muramatsu, F., Kidoya, H., Naito, H., Sakimoto, S. & Takakura, N. microRNA-125b inhibits tube formation of blood vessels through translational suppression of VE-cadherin. Oncogene 32, 414–421 (2013).

    Google Scholar 

  46. Song, B., Xu, J., Zhong, P. & Fang, L. MiR-125a-5p silencing inhibits cerebral ischemia-induced injury through targeting IGFBP3. Folia Neuropathol. 59, 121–130 (2021).

    Google Scholar 

  47. Zhao, Y. Y., Wang, W. A. & Hu, H. Treatment with recombinant tissue plasminogen activator alters the microRNA expression profiles in mouse brain after acute ischemic stroke. Neurol. Sci. 36, 1463–1470 (2015).

    Google Scholar 

  48. Liu, R., Luo, S., Zhang, Y. S. & Tsang, C. K. Plasma metabolomic profiling of patients with transient ischemic attack reveals positive role of neutrophils in ischemic tolerance. EBioMedicine 97, 104845 (2023).

    Google Scholar 

  49. Karam, R. A., Amer, M. M. & Zidan, H. E. Long noncoding RNA NEAT1 expression and its target miR-124 in diabetic ischemic stroke patients. Genet. Test. Mol. Biomarkers 26, 398–407 (2022).

    Google Scholar 

  50. Zhou, X. & Qi, L. miR-124 Is downregulated in serum of acute cerebral infarct patients and shows diagnostic and prognostic value. Clin. Appl. Thromb. Hemost. 27, 10760296211035446 (2021).

    Google Scholar 

  51. Bombaci, A. et al. Early-phase fluid diagnostic biomarkers in acute ischemic stroke: An umbrella review. medRxiv (2025) https://doi.org/10.1101/2025.07.09.25331017.

  52. Popa, D.-I. et al. Performance of GFAP and UCH-L1 for early acute stroke diagnosis in the emergency department. J. Clin. Med. 14, 4746 (2025).

    Google Scholar 

  53. Rashidian, J. et al. Cell cycle machinery and stroke. Biochimica et Biophysica Acta (BBA) – Mol. Basis Dis. 1772, 484–493 (2007).

    Google Scholar 

  54. Becker, E. B. E. & Bonni, A. Beyond proliferation–cell cycle control of neuronal survival and differentiation in the developing mammalian brain. Semin. Cell Dev. Biol. 16, 439–448 (2005).

    Google Scholar 

  55. Hua, Y., Zhang, W., Xie, Z., Xu, N. & Lu, Y. MMP-2 is mainly expressed in arterioles and contributes to cerebral vascular remodeling associated with TGF-β1 signaling. J. Mol. Neurosci. 59, 317–325 (2016).

    Google Scholar 

  56. Bobik, A. Transforming growth factor-betas and vascular disorders. Arterioscler. Thromb. Vasc. Biol. 26, 1712–1720 (2006).

    Google Scholar 

  57. Gao, H., Yang, L. & Shao, Y. SIRT1 / NF-κB pathway on neuronal apoptosis in rats with ischemic stroke. Cell. Mol. Biol. 68, 77–82 (2022).

    Google Scholar 

  58. Bruna, B. et al. The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca signals, ERK and PI3K. Biochem. Biophys. Res. Commun. 505, 201–207 (2018).

    Google Scholar 

  59. Farina, M., Vieira, L. E., Buttari, B., Profumo, E. & Saso, L. The Nrf2 pathway in ischemic stroke: A review. Molecules 26, 5001 (2021).

    Google Scholar 

  60. Le Blanc, J. et al. Platelets selectively regulate the release of BDNF, but not that of its precursor protein, proBDNF. Front. Immunol. 11, 575607 (2020).

    Google Scholar 

  61. Want, A., Nan, X., Kokkali, E., Barde, Y. A. & Morgan, J. E. Brain-derived neurotrophic factor released from blood platelets prevents dendritic atrophy of lesioned adult central nervous system neurons. Brain Commun. 5, fcad046 (2023).

    Google Scholar 

  62. Chen, A. I., Xiong, L.-J., Tong, Y. U. & Mao, M. The neuroprotective roles of BDNF in hypoxic ischemic brain injury. Biomed. Rep. 1, 167 (2012).

    Google Scholar 

  63. Mourão, A. M. et al. Plasma levels of brain-derived neurotrophic factor are associated with prognosis in the acute phase of ischemic stroke. J. Stroke Cerebrovasc. Dis. 28, 735–740 (2019).

    Google Scholar 

  64. Maisonpierre, P. C. et al. Human and rat brain-derived neurotrophic factor and neurotrophin-3: Gene structures, distributions, and chromosomal localizations. Genomics 10, 558–568 (1991).

    Google Scholar 

  65. Zhu, H. et al. Interleukins and ischemic stroke. Front. Immunol. 13, 828447 (2022).

    Google Scholar 

  66. Armstead, W. M. et al. Retraction note: Release of IL-6 after stroke contributes to impaired cerebral autoregulation and hippocampal neuronal necrosis through NMDA receptor activation and upregulation of ET-1 and JNK. Transl. Stroke Res. https://doi.org/10.1007/s12975-024-01264-7 (2024).

    Google Scholar 

  67. Kerkis, I., da Silva, Á. P. & Araldi, R. P. The impact of interleukin-6 (IL-6) and mesenchymal stem cell-derived IL-6 on neurological conditions. Front. Immunol. 15, 1400533 (2024).

    Google Scholar 

  68. Webb, C. E., Vautrinot, J. & Hers, I. IL-6 as a mediator of platelet hyper-responsiveness. Cells 14, 766 (2025).

    Google Scholar 

  69. Pawluk, H. et al. The role of IL-6 in ischemic stroke. Biomolecules 15, 470 (2025).

    Google Scholar 

  70. Ot, S., Zafar, L., Beg, M. & Siddiqui, O. A. Association of mean platelet volume with risk factors and functional outcome in acute ischemic stroke. J. Neurosci. Rural Pract. 12, 764–769 (2021).

    Google Scholar 

  71. Cramer, S. C. An overview of therapies to promote repair of the brain after stroke. Head Neck 33(Suppl 1), S5-7 (2011).

    Google Scholar 

  72. Bhattarai, P. et al. Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease. Acta Neuropathol. 147, 1–20 (2024).

    Google Scholar 

  73. Phillips, C. M., Stamatovic, S. M., Keep, R. F. & Andjelkovic, A. V. Epigenetics and stroke: role of DNA methylation and effect of aging on blood–brain barrier recovery. Fluids Barriers CNS 20, 14 (2023).

    Google Scholar 

  74. Howe, M. D. et al. Fibronectin induces the perivascular deposition of cerebrospinal fluid-derived amyloid-β in aging and after stroke. Neurobiol. Aging 72, 1 (2018).

    Google Scholar 

  75. Dhanesha, N. et al. Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but not endothelial cells, exacerbates stroke outcome by promoting thrombo-inflammation. Stroke 50, 1201–1209 (2019).

    Google Scholar 

  76. Prakash, P., Kulkarni, P. P., Lentz, S. R. & Chauhan, A. K. Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4. Blood 125, 3164–3172 (2015).

    Google Scholar 

  77. Maurer, E. et al. Fibrillar cellular fibronectin supports efficient platelet aggregation and procoagulant activity. Thromb. Haemost. 114, 1175–1188 (2015).

    Google Scholar 

  78. American Heart Association Journals. American Heart Association Journals https://www.ahajournals.org/doi/abs/https://doi.org/10.1161/JAHA.125.044299.

  79. Zhai, Z. et al. Fibrinogen controls human platelet fibronectin internalization and cell-surface retention. J. Thromb. Haemost. 5, 1740–1746 (2007).

    Google Scholar 

  80. Mosher, D. F. Adding complexity to fibronectin-platelet interactions. Arterioscler. Thromb. Vasc. Biol. 28, 203–204 (2008).

    Google Scholar 

  81. Krupinski, J., Kumar, P., Kumar, S. & Kaluza, J. Increased expression of TGF-beta 1 in brain tissue after ischemic stroke in humans. Stroke 27, 852 (1996).

    Google Scholar 

  82. Kim, Y. & Lee, C. The gene encoding transforming growth factor β1 confers risk of ischemic stroke and vascular dementia. Stroke https://doi.org/10.1161/01.STR.0000244782.76917.87 (2006).

    Google Scholar 

  83. Moustakas, A. & Miyazawa, K. TGF-β in Human Disease. (Springer Science & Business Media, 2013).

  84. Popek, M., Bobula, B., Orzeł-Gajowik, K. & Zielińska, M. The effect of TGF-β1 reduced functionality on the expression of selected synaptic proteins and electrophysiological parameters: Implications of changes observed in acute hepatic encephalopathy. Int. J. Mol. Sci. 23, 1081 (2022).

    Google Scholar 

  85. Hewitt, B. J., Ali, M., Hubbard, J., Hill, L. J. & Botfield, H. Systematic review of the differential effects of TGF-β1 in ischemic and hemorrhagic preclinical stroke models. J. Am. Heart Assoc. 14, e037890 (2025).

    Google Scholar 

  86. Zhang, L. et al. Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-β/Smad2/3 pathway. Cell Death Dis. 12, 1068 (2021).

    Google Scholar 

  87. Li, F., Kang, X., Xin, W. & Li, X. The emerging role of extracellular vesicle derived from neurons/neurogliocytes in central nervous system diseases: Novel insights into ischemic stroke. Front. Pharmacol. 13, 890698 (2022).

    Google Scholar 

  88. Serralheiro, P., Soares, A., Costa Almeida, C. M. & Verde, I. TGF-β1 in vascular wall pathology: Unraveling chronic venous insufficiency pathophysiology. Int. J. Mol. Sci. 18, 2534 (2017).

    Google Scholar 

  89. Spakova, T., Janockova, J. & Rosocha, J. Characterization and therapeutic use of extracellular vesicles derived from platelets. Int. J. Mol. Sci. 22, 9701 (2021).

    Google Scholar 

  90. Yan, J. et al. Platelet-derived microvesicles promote endothelial progenitor cell proliferation in intimal injury by delivering TGF-β1. FEBS J. 287, 5196–5217 (2020).

    Google Scholar 

  91. Wang, L., Chen, Y., Feng, D. & Wang, X. Serum ICAM-1 as a predictor of prognosis in patients with acute ischemic stroke. Biomed. Res. Int. 2021, 5539304 (2021).

    Google Scholar 

  92. Stegner, D., Klaus, V. & Nieswandt, B. Platelets as modulators of cerebral ischemia/reperfusion injury. Front. Immunol. 10, 488721 (2019).

    Google Scholar 

  93. Couch, Y. Differential effects of ischemia and inflammation on plasma-derived extracellular vesicle characteristics and function. (2025) https://doi.org/10.21203/rs.3.rs-6937248/v1

  94. Yin, P., Wei, Y., Wang, X., Zhu, M. & Feng, J. Roles of specialized pro-resolving lipid mediators in cerebral ischemia reperfusion injury. Front. Neurol. 9, 378492 (2018).

    Google Scholar 

  95. Li, C. et al. Cerebral endothelial cell-derived small extracellular vesicles enhance neurovascular function and neurological recovery in rat acute ischemic stroke models of mechanical thrombectomy and embolic stroke treatment with tPA. J. Cereb. Blood Flow Metab. https://doi.org/10.1177/0271678X21992980 (2021).

    Google Scholar 

  96. Gesuete, R., Kohama, S. G. & Stenzel-Poore, M. Toll-like receptors and ischemic brain injury. J. Neuropathol. Exp. Neurol. 73, 378 (2014).

    Google Scholar 

  97. Shichita, T. et al. Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke. J. Neurochem. 123(Suppl 2), 29–38 (2012).

    Google Scholar 

  98. Rao, D., Sang, C., Lai, Z., Zhong, J. & Tang, Z. Roles of extracellular vesicles in cerebral protection of ischemic stroke. Neuro Endocrinol. Lett. 42, 160 (2021).

    Google Scholar 

  99. Roseborough, A. D. et al. Plasma derived extracellular vesicle biomarkers of microglia activation in an experimental stroke model. J. Neuroinflam. 20, 20 (2023).

    Google Scholar 

  100. Qiu, L. et al. Mesenchymal stem cell-derived extracellular vesicles attenuate tPA-induced blood-brain barrier disruption in murine ischemic stroke models. Acta Biomater. 154, 424–442 (2022).

    Google Scholar 

  101. Ding, N. et al. Toll-like receptor 4 regulates platelet function and contributes to coagulation abnormality and organ injury in hemorrhagic shock and resuscitation. Circ. Cardiovasc. Genet. 7, 615–624 (2014).

    Google Scholar 

  102. de Rezende, V. L. et al. The role of extracellular vesicles in brain-peripheral communication following ischemic stroke: Implications for neural repair and regeneration. J. Neurochem. 169, e70155 (2025).

    Google Scholar 

  103. Weinstein, J. R. et al. Functional polymorphisms in toll-like receptor 4 are associated with worse outcome in acute ischemic stroke patients. NeuroReport 25, 580 (2014).

    Google Scholar 

  104. Sun, M. et al. Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation. Sci. Rep. 5, 11445 (2015).

    Google Scholar 

  105. Suzuki, Y. et al. Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia. Sci. Rep. 2, 896 (2012).

    Google Scholar 

  106. Krug, T. et al. TTC7B emerges as a novel risk factor for ischemic stroke through the convergence of several genome-wide approaches. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 32, 1061 (2012).

    Google Scholar 

  107. Fjdm, M. et al. Transcriptomic Analysis of Extracellular Vesicles in the Search for Novel Plasma and Thrombus Biomarkers of Ischemic Stroke Etiologies. Int. J. Mol. Sci. 25, 4379 (2024).

    Google Scholar 

  108. Kanki, H. et al. Importance of microRNAs by mRNA-microRNA integration analysis in acute ischemic stroke patients. J. Stroke Cerebrovasc. Dis.: Off. J. Natl. Stroke Assoc. 32(9), 107277 (2023).

    Google Scholar 

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Acknowledgements

This work was written by the members (MP, DMG, CE, ZW) of the International and Intercontinental Cardiovascular and Cardiometabolic Research Team (I-COMET; www.icomet.science).

Funding

MP was supported financially as part of the research grant ‘OPUS’ from National Science Center, Poland (grant number 2018/31/B/NZ7/01137) and Medical University of Warsaw (grant number 1M9/2/M/MBM/N/21).

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Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, Banacha 1B Str., 02-097, Warsaw, Poland

    Ceren Eyileten, Zofia Wicik, Sara Ahmadova, Pamela Czajka, Dagmara Mirowska-Guzel, Anna Czlonkowska & Marek Postula

  2. Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland

    Ceren Eyileten

  3. Department of Experimental and Clinical Neuroscience, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957, Warsaw, Poland

    Zofia Wicik

  4. Department of Medical Pharmacology, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Andleeb Shahzadi

  5. Doctoral School, Medical University of Warsaw, Warsaw, Poland

    Pamela Czajka

  6. Department of Neurology, Faculty of Medicine and Dentistry, Medical University of Warsaw, Warsaw, Poland

    Izabela Domitrz & Agata Wierzchowska-Ciok

  7. 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02-957, Warsaw, Poland

    Anna Czlonkowska

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Contributions

Writing—original draft preparation, CE, PC, ZW, MP; writing—review and editing, CE, PC, ZW, AS, DMG, AC, MP, ID, AWC, SA; bioinformatic analysis– ZW, visualization, CE, ZW; supervision, CE, DMG, MP; laboratory and computer analysis, CE, SA; Data preparation; CE, ID, AWC. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Ceren Eyileten.

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Competing interests

Authors declare no conflict of interest related to this work.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of Medical University of Warsaw, Warsaw, Poland (protocol code KB/148/2017, date of approval: 4 July 2017).

Informed consent

Informed consent was obtained from all subjects involved in the study and written informed consent has been obtained from the patient(s) to publish this paper.

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Cite this article

Eyileten, C., Wicik, Z., Shahzadi, A. et al. An integrative clinical and bioinformatic analysis identifies MicroRNAs as biomarkers of ischemic stroke severity. Sci Rep (2026). https://doi.org/10.1038/s41598-026-36494-2

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  • Received: 11 December 2024

  • Accepted: 13 January 2026

  • Published: 26 January 2026

  • DOI: https://doi.org/10.1038/s41598-026-36494-2

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Keywords

  • Ischemic stroke
  • microRNA
  • Biomarker
  • Diagnostic
  • Disease severity
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