Metabolomics Reveals Key Biomarkers for Ischemic Stroke: A Systematic Review of Emerging Evidence

Lu Ding¹Meiling Zhang²Baochao Fan²Fuyuan Deng²Zhenyuan Li³Yifan Wu⁴Jingchun Zeng^5*Liming Lu^6*

• ¹Department of Traditional Chinese Medicine, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, Hangzhou, China
• ²Clinical Research and Big Data Laboratory, South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangzhou University of Chinese Medicine, Guangzhou, China
• ³Medical department, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, Hangzhou, China
• ⁴China Rihabilitation Research Center, Beijing, China
• ⁵Department of Rehabilitation, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China, Guangzhou, China
• ⁶Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China

Objective: To systematically collate and evaluate metabolomics-based biomarkers of ischemic stroke (IS) to guide clinical diagnosis and treatment.Methods: Comprehensive 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.A 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.This 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.