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Extracellular vesicles (EVs), which include apoptotic bodies, microvesicles, and exosomes, have emerged alongside metabolomics as active mediators of intercellular communication, transporting diverse cargo that mirrors the cellular origin and metabolic status of their parent cell. EVs are enriched with lipids, proteins, nucleic acids, and biologically active metabolites involve in signal transduction, metabolic regulation, and pathogenic mechanisms of a disease. Nevertheless issues related to heterogeneity of vesicles, purity of isolation, and detection sensitivity of metabolites, the study of EV metabolomics still methodologically and analytically challenging. This review offers a critical synthesis of current knowledge in EV metabolomics including analytical technology, statistical and computational approaches, and emerging clinical applications. In addition, a specific focus on methodological variability, contamination chances, and limitations in existing research study design that affect reproducibility and translation. Furthermore, multi-omics integration and machine learning are reviewed as promising approaches to enhance the discovery of biomarkers and interpretation of the biological system. Finally, highlighting the key research gap and future research directions to steer the advancement of clinically related applications in translational medicine.<\/jats:p>","DOI":"10.1177\/15578100261467517","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:53:08Z","timestamp":1784029988000},"page":"561-570","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Human Extracellular Vesicles, Metabolites, and Metabolomics: A Comprehensive Review"],"prefix":"10.1177","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6062-3662","authenticated-orcid":false,"given":"Mohammed A.","family":"Al-zubaidi","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11142229"},{"key":"e_1_3_3_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomethods\/bpae009"},{"key":"e_1_3_3_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-91129-y"},{"key":"e_1_3_3_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25021205"},{"key":"e_1_3_3_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25052730"},{"key":"e_1_3_3_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/138945012800564095"},{"key":"e_1_3_3_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-023-05383-0"},{"key":"e_1_3_3_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25084490"},{"key":"e_1_3_3_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/2025.09.04.674190"},{"key":"e_1_3_3_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.3c07427"},{"key":"e_1_3_3_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16223729"},{"key":"e_1_3_3_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom16040533"},{"key":"e_1_3_3_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology9010021"},{"key":"e_1_3_3_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00155.2025"},{"key":"e_1_3_3_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-006-0037-z"},{"key":"e_1_3_3_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c18110"},{"key":"e_1_3_3_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2014.04.003"},{"key":"e_1_3_3_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2024.120010"},{"key":"e_1_3_3_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21228550"},{"key":"e_1_3_3_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3169"},{"key":"e_1_3_3_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-023-01973-5"},{"key":"e_1_3_3_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trac.2021.116382"},{"key":"e_1_3_3_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02332-0"},{"key":"e_1_3_3_25_1","first-page":"28","article-title":"Interconnections within the tumor microenvironment: Extracellular vesicles as critical players of metabolic reprogramming in tumor cells","volume":"10","author":"Encarna\u00e7\u00e3o CC","year":"2024","unstructured":"Encarna\u00e7\u00e3o CC, , Faria GM, , Franco VA, , Botelho LG, , Moraes JA, , Renovato-Martins M. 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