Metabolomics reveals key biomarkers for ischemic stroke: a systematic review of emerging evidence

Lu Ding; Meiling Zhang; Baochao Fan; Fuyuan Deng; Zhenyuan Li; Yixuan Han; Yong Wu; Jingchun Zeng; Liming Lu

doi:10.3389/fneur.2025.1630390

journal article Open Access Aug 08, 2025

Metabolomics reveals key biomarkers for ischemic stroke: a systematic review of emerging evidence

Lu Ding

Meiling Zhang

Baochao Fan Fuyuan Deng Zhenyuan Li Yixuan Han Yong Wu

Jingchun Zeng Liming Lu

Frontiers in Neurology Vol. 16 · Frontiers Media SA

View at Publisher Save 10.3389/fneur.2025.1630390

Abstract

ObjectiveTo systematically collate and evaluate metabolomics-based biomarkers of ischemic stroke (IS) to guide clinical diagnosis and treatment.MethodsComprehensive literature searches were conducted in PubMed, Embase, and Web of Science using “IS” and “metabolomics” as core keywords, covering publications up through February 2024. Any original metabolomic research related to IS was selected. Key information such as study demographics, study type, objectives, metabolomic analysis methods, and main findings were extracted and analyzed. Frequently mentioned metabolites were subjected to enrichment analysis using the MetaboAnalyst 6.0 platform.ResultsA total of 51 studies were included. Quality assessment revealed that 54.8% of the diagnostic studies and 69.2% of the prognostic studies were high-quality, with most controlling for confounding factors. Metabolite analysis revealed associations between decreased proline, isoleucine, valine, and alanine levels with IS. Increased tyrosine, glutamine, phenylalanine, sphingomyelin, glutamate, lactate and glucose, and decreased LysoPC (18:2), histidine, and methionine levels were linked to IS onset. Specific metabolite combinations, such as serine, isoleucine, betaine, PC (5:0/5:0), and LysoPE (18:2), showed high precision in predicting acute ischemic stroke (AIS) (training set AUC = 0.988, test set AUC = 0.971). Glycine-serine-threonine and valine-leucine-isoleucine pathways were significant in diagnosing IS and AIS, and in differentiating ischemic and hemorrhagic strokes, as well as identifying post-stroke depression and cognitive impairment.ConclusionThis study confirms the potential diagnostic and prognostic value of changes in amino acids and lipids, as well as other metabolites and metabolic pathways, in IS. These findings highlight the promise of metabolomics in IS diagnosis, differential diagnosis, risk assessment, and complication identification. However, further validation is needed due to the varying quality of the included studies.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#myprospero, identifier CRD42022335505.

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References

85

[1]

Barthels "Current advances in ischemic stroke research and therapies" Biochim Biophys Acta (2020) 10.1016/j.bbadis.2018.09.012

[2]

Latchaw "Recommendations for imaging of acute ischemic stroke: a scientific statement from the American Heart Association" Stroke (2009) 10.1161/strokeaha.108.192616

[3]

Miyamoto "Stroke classification and treatment support system artificial intelligence for usefulness of stroke diagnosis" Front Neurol (2023) 10.3389/fneur.2023.1295642

[4]

Jickling "Biomarker panels in ischemic stroke" Stroke (2015) 10.1161/strokeaha.114.005604

[5]

Metabolomics and metabolites in ischemic stroke

Maria S. Chumachenko, Tatsiana V. Waseem, Sergei V. Fedorovich

Reviews in the Neurosciences 2022 10.1515/revneuro-2021-0048

[6]

Zhang "Single-cell microwell platform reveals circulating neural cells as a clinical indicator for patients with blood-brain barrier breakdown" Research (2021) 10.34133/2021/9873545

[7]

Wishart "Emerging applications of metabolomics in drug discovery and precision medicine" Nat Rev Drug Discov (2016) 10.1038/nrd.2016.32

[8]

Chen "Single-cell RNA transcriptomics and multi-omics analyses reveal the clinical effects of acupuncture on methadone reduction" Res (2025) 10.34133/research.0741

[9]

Ivanisevic "The role of metabolomics in brain metabolism research" J Neuroimmune Pharmacol (2015) 10.1007/s11481-015-9621-1

[10]

Yu "Identification of three potential novel biomarkers for early diagnosis of acute ischemic stroke via plasma lipidomics" Metabolomics (2023) 10.1007/s11306-023-01990-3

[11]

Wang "Targeted metabolomic profiling reveals association between altered amino acids and poor functional recovery after stroke" Front Neurol (2020) 10.3389/fneur.2019.01425

[12]

Powers "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 (2019) 10.1161/str.0000000000000211

[13]

Lumbreras "QUADOMICS: an adaptation of the Quality Assessment of Diagnostic Accuracy Assessment (QUADAS) for the evaluation of the methodological quality of studies on the diagnostic accuracy of ‘-omics’-based technologies" Clin Biochem (2008) 10.1016/j.clinbiochem.2008.06.018

[14]

Hayden "Assessing bias in studies of prognostic factors" Ann Intern Med (2013) 10.7326/0003-4819-158-4-201302190-00009

[15]

Xia "Metaboanalyst: a web server for metabolomic data analysis and interpretation" Nucleic Acids Res (2009) 10.1093/nar/gkp356

[16]

Xia "MetaboAnalyst 3.0—making metabolomics more meaningful" Nucleic Acids Res (2015) 10.1093/nar/gkv380

[17]

Chen "Serum metabonomics reveals risk factors in different periods of cerebral infarction in humans" Front Mol Biosci (2022) 10.3389/fmolb.2021.784288

[18]

Chi "Untargeted metabolomics predicts the functional outcome of ischemic stroke" J Formos Med Assoc (2021) 10.1016/j.jfma.2020.04.026

[19]

Liu "Discovery of metabolite biomarkers for acute ischemic stroke progression" J Proteome Res (2017) 10.1021/acs.jproteome.6b00779

[20]

Sun "Discovery of a new biomarker pattern for differential diagnosis of acute ischemic stroke using targeted metabolomics" Front Neurol (2019) 10.3389/fneur.2019.01011

[21]

Pivotal interplays between fecal metabolome and gut microbiome reveal functional signatures in cerebral ischemic stroke

Lanlan Zhao, Chao Wang, Shanxin Peng et al.

Journal of Translational Medicine 2022 10.1186/s12967-022-03669-0

[22]

Floegel "Serum metabolites and risk of myocardial infarction and ischemic stroke: a targeted metabolomic approach in two German prospective cohorts" Eur J Epidemiol (2018) 10.1007/s10654-017-0333-0

[23]

Jové "Metabolomics predicts stroke recurrence after transient ischemic attack" Neurology (2015) 10.1212/wnl.0000000000001093

[24]

Kong "Predictive serum biomarkers of patients with cerebral infarction" Neurol Res (2022) 10.1080/01616412.2021.1987055

[25]

Oliveira "Searching for metabolic markers of stroke in human plasma via NMR analysis" Int J Mol Sci (2023) 10.3390/ijms242216173

[26]

Seo "Medium-chain acylcarnitines are associated with cardioembolic stroke and stroke recurrence" Arterioscler Thromb Vasc Biol (2018) 10.1161/atvbaha.118.311373

[27]

Huang "Characteristic metabolic and microbial profiles in acute ischemic stroke patients with phlegm-heat pattern" J Tradit Chin Med Sci (2023) 10.1016/j.jtcms.2023.06.001

[28]

Jiang "A metabonomic approach applied to predict patients with cerebral infarction" Talanta (2011) 10.1016/j.talanta.2011.01.015

[29]

Poupore "Metabolomic profiles of men and women ischemic stroke patients" Diagnostics (2021) 10.3390/diagnostics11101786

[30]

Qi "Metabolomic characterization of acute ischemic stroke facilitates metabolomic biomarker discovery" Appl Biochem Biotechnol (2022) 10.1007/s12010-022-04024-1

[31]

Sidorov "Difference in acute and chronic stage ischemic stroke metabolic markers with controls" J Stroke Cerebrovasc Dis (2023) 10.1016/j.jstrokecerebrovasdis.2023.107211

[32]

Wang "Changes of metabolites in acute ischemic stroke and its subtypes" Front Neurosci (2021) 10.3389/fnins.2020.580929

[33]

Zhang "Distinguishing intracerebral hemorrhage from acute cerebral infarction through metabolomics" Rev Investig Clin (2017) 10.24875/ric.17002348

[34]

Jung "1h-NMR-based metabolomics study of cerebral infarction" Stroke (2011) 10.1161/strokeaha.110.598789

[35]

Kimberly "Metabolite profiling identifies a branched chain amino acid signature in acute cardioembolic stroke" Stroke (2013) 10.1161/strokeaha.111.000397

[36]

Grandizoli "Ischemic stroke progress evaluation by 3 1P NMR-based metabonomic of human serum" J Braz Chem Soc (2014) 10.5935/0103-5053.20140084

[37]

Hu "Rapid and sensitive differentiating ischemic and hemorrhagic strokes by dried blood spot based direct injection mass spectrometry metabolomics analysis" J Clin Lab Anal (2016) 10.1002/jcla.21943

[38]

Huang "UPLC-QTOF-MS-based metabolomics study on ischemic stroke patients" Chem J Chin Univ (2017) 10.7503/cjcu20170153

[39]

Sun "Potential serum biomarkers and metabonomic profiling of serum in ischemic stroke patients using UPLC/Q-TOF MS/MS" PLoS One (2017) 10.1371/journal.pone.0189009

[40]

Wang "GC-MS-based metabolomics identifies an amino acid signature of acute ischemic stroke" Neurosci Lett (2017) 10.1016/j.neulet.2017.01.039

[41]

Li "Identification of potential diagnostic biomarkers of cerebral infarction using gas chromatography-mass spectrometry and chemometrics" RSC Adv (2018) 10.1039/c8ra03132k

[42]

Goulart "Amino acid biosignature in plasma among ischemic stroke subtypes" Biomed Res Int (2019) 10.1155/2019/8480468

[43]

Sun "A prospective study of serum metabolites and risk of ischemic stroke" Neurology (2019) 10.1212/wnl.0000000000007279

[44]

Tiedt "Circulating metabolites differentiate acute ischemic stroke from stroke mimics" Ann Neurol (2020) 10.1002/ana.25859

[45]

Yu "Association of plasma metabolic biomarker sphingosine-1-phosphate with cerebral collateral circulation in acute ischemic stroke" Front Physiol (2021) 10.3389/fphys.2021.720672

[46]

Yu "Phenylacetylglutamine, a novel biomarker in acute ischemic stroke" Front Cardiovasc Med (2021) 10.3389/fcvm.2021.798765

[47]

Balasubramanian "Metabolomic profiles associated with incident ischemic stroke" Neurology (2022) 10.1212/wnl.0000000000013129

[48]

Chen "Related factors based on non-targeted metabolomics methods in minor ischaemic stroke" Front Endocrinol (2022) 10.3389/fendo.2022.952918

[49]

Djite "A metabolomic signature of ischemic stroke showing acute oxidative and energetic stress" Antioxidants (2023) 10.3390/antiox13010060

[50]

Yadav "Nmr based serum metabolomics revealed metabolic signatures associated with oxidative stress and mitochondrial damage in brain stroke" Metab Brain Dis (2023) 10.1007/s11011-023-01331-2

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Published: Aug 08, 2025
Vol/Issue: 16
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Authors

State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, China; Sino German Joint Research Institute, Nanchang University, Nanchang 330047, China; Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang 330047, China

Funding

National Natural Science Foundation of China Award: 82174527

Cite This Article

Lu Ding, Meiling Zhang, Baochao Fan, et al. (2025). Metabolomics reveals key biomarkers for ischemic stroke: a systematic review of emerging evidence. Frontiers in Neurology, 16. https://doi.org/10.3389/fneur.2025.1630390

Metabolomics reveals key biomarkers for ischemic stroke: a systematic review of emerging evidence

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