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Circulating extracellular vesicles (EVs) in plasma, as a noninvasive diagnostic carrier, have caused widely concern. Here, a novel oxylipidomic profiling was used to analysis the HCC patients\u2019 tissue\u2010derived EVs (TD\u2010EVs) cargo and revealing\u00a0differentially expressed oxylipins\u00a0(vs. adjacent tissues,\u00a0\n                    <jats:italic>p<\/jats:italic>\n                    &lt;0.05), which undetected in bulk tissues. The hub oxylipins 13(S)\u2010HODE discovered in TD\u2010EVs was validated in plasma derived EVs (PD\u2010EVs) by using single\u2010molecule analysis platform, showing\u00a0superior efficacy in AFP\u2010negative HCC patients\u00a0(AUC = 0.8474\u00a0vs. 0.7627 in AFP\u2010positive). Clinically, machine learning integrating EV\u2010derived 13(S)\u2010HODE with routine clinical parameters of HCC patients was developed to optimize diagnostic classification. The machine learning model, LightGBM, achieved outstanding performance: AUC_mean = 0.962, Sensitivity = 0.933 (0.660\u20130.997), Specificity: 0.957(0.760\u20130.998), 95%CI: 0.958\u20131.000 in multi\u2010group classification of HCC diagnostics, demonstrating the enhanced diagnostic efficiency of 13(S)\u2010HODE positive EV subpopulation with other clinical data. This study\u00a0firstly establishes EV\u2010derived 13(S)\u2010HODE as a concordantly biomarker across tissue and plasma sources. Furthermore, single\u2010molecule analysis platform offers it a\u00a0highly sensitive diagnostic performance for HCC, particularly valuable for AFP\u2010negative HCC subgroup.\n                  <\/jats:p>","DOI":"10.1002\/jev2.70368","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:27:16Z","timestamp":1789709236000},"source":"Crossref","is-referenced-by-count":0,"title":["Oxylipins\u2010Omics Combine With Single\u2010Molecule Analysis Identifies 13(S)\u2010HODE Positive Extracellular Vesicles as a Diagnostic Biomarker for AFP\u2010Negative Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7060-2953","authenticated-orcid":false,"given":"Yu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Laboratory Nanfang Hospital Southern Medical University Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Single\u2010cell and Extracellular Vesicles Nanfang Hospital Southern Medical University Guangzhou P. R. China"},{"name":"Department of Hepatobiliary Surgery Nanfang Hospital Southern Medical University Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoting","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Nanfang Hospital Southern Medical University Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Single\u2010cell and Extracellular Vesicles Nanfang Hospital Southern Medical University Guangzhou P. R. China"},{"name":"Department of Hepatobiliary Surgery Nanfang Hospital Southern Medical University Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixian","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Laboratory Nanfang Hospital Southern Medical University Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Single\u2010cell and Extracellular Vesicles Nanfang Hospital Southern Medical University Guangzhou P. R. 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