{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:31:45Z","timestamp":1792009905094,"version":"4.4.0"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dutch Digestive Health Fund","award":["WO 21-03"],"award-info":[{"award-number":["WO 21-03"]}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","award":["68328655"],"award-info":[{"award-number":["68328655"]}],"id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing in both prevalence and severity, highlighting the need for non-invasive biomarkers to assess disease activity. Extracellular vesicles (EVs), which carry molecular cargo from their cells of origin, hold promise as accessible biomarkers. We performed proteomic profiling of plasma-derived EVs from 70 patients with MASLD to identify protein signatures associated with key histological features (steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and fibrosis). These proteins were subsequently correlated with magnetic resonance (MR)-based liver imaging. Plasma EV protein profile differed between mild (S1) and advanced steatosis (S3). H4C1, OIT3, and ANPEP were elevated in S3, while CCDC25 and KLHL41 were decreased (|log2 fold change| &gt; 1, p &lt; 0.05). KLHL41 had a weak-to-moderate correlation with proton density fat fraction (PDFF) (R = \u22120.34, p = 0.016). GP1BA was upregulated in MASH (log2 fold change = 1.13, p = 0.03) but showed weak correlation with cT1, an imaging parameter for steatohepatitis (R = 0.22, p = 0.173). In fibrosis, complement component 7 (C7) was elevated in advanced (\u2265F3) vs. mild fibrosis (&lt;F2) (log2 fold change = 0.95, adjusted p = 0.002) and correlated with MR elastography-derived liver stiffness (R = 0.38, p = 0.004). The AUC of C7 for differentiating &lt;F2 vs. \u2265F2 and &lt;F3 vs. \u2265F3 was 0.80 (95% CI: 0.69\u20130.91) and 0.83 (95% CI: 0.72\u20130.93), respectively. In conclusion, plasma EVs contain distinct protein signatures associated with steatosis, steatohepatitis, and fibrosis in MASLD. These preliminary findings support the potential utility of plasma EVs as non-invasive biomarkers and provide insights into disease pathophysiology. However, further validation in larger, independent cohorts is necessary to confirm these associations and establish their clinical relevance.<\/jats:p>","DOI":"10.3390\/biom15111596","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T09:06:36Z","timestamp":1763111196000},"page":"1596","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Plasma Extracellular Vesicles Contain Protein Biomarkers for Capturing Stages of Metabolic Dysfunction-Associated Steatotic Liver Disease: A Preliminary Exploratory Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8717-6476","authenticated-orcid":false,"given":"Yakun","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen C. van","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1005 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Serna-Salas","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0066-3720","authenticated-orcid":false,"given":"Justina C.","family":"Wolters","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3668-944X","authenticated-orcid":false,"given":"Nienke P. M.","family":"Wassenaar","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stan","family":"Driessen","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Linde","family":"Mak","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marieke van","family":"Dijk","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veera A. T.","family":"Houttu","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia J.","family":"Witjes","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diona","family":"Zwirs","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8611-840X","authenticated-orcid":false,"given":"Michail","family":"Doukas","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus University Medical Center, Erasmus University Rotterdam, Molewaterplein 40, 3015 CN Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1283-630X","authenticated-orcid":false,"given":"Joanne","family":"Verheij","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3844-5254","authenticated-orcid":false,"given":"Robin P. F.","family":"Dullaart","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4240-7506","authenticated-orcid":false,"given":"Hans","family":"Blokzijl","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriaan G.","family":"Holleboom","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4764-0246","authenticated-orcid":false,"given":"Han","family":"Moshage","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.3350\/cmh.2024.0431","article-title":"Epidemiology of Metabolic Dysfunction-Associated Steatotic Liver Disease","volume":"31","author":"Younossi","year":"2024","journal-title":"Clin. 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