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This pilot study aims to investigate the potential of plasma circulating microRNAs (miRNAs) as predictive biomarkers for clinical responses to dimethyl fumarate (DMF), a widely used oral treatment for MS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Peripheral blood samples were collected from nineteen treatment\u2010na\u00efve people with relapsing\u2013remitting MS (pwRRMS) before and after 3, 6, 12, and 24\u2009months of DMF administration, as well as from nineteen healthy individuals. MiRNAs were quantified by RT\u2010qPCR after plasma RNA extraction, and peripheral blood immune cells were analyzed by flow cytometry. Pathway enrichment and protein\u2013protein interaction analyses were performed to identify the biological processes and molecular networks associated with mRNAs targeted by the specific DMF\u2010modulated miRNAs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a DMF\u2010modulated miRNA signature with significant changes occurring at early treatment stages. Notably, specific miRNAs were correlated with both clinical and immunological outcomes upon DMF treatment, including lymphocyte count reduction (let\u20107b\u20105p and miR\u2010223\u20103p) and disease progression over 2\u2009years (miR\u2010223\u20103p, miR\u201023a\u20103p, miR\u201023b\u20103p, miR\u201027a\u20103p, and miR\u201027b\u20103p), suggesting their potential as predictive biomarkers for treatment response. Moreover, the validated mRNA targets of DMF\u2010modulated miRNAs were enriched for IL\u20106 signaling and NRF2\u2010dependent antioxidant pathways, highlighting the potential molecular mechanisms underpinning DMF efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This small exploratory study underscores the potential of plasma circulating miRNAs as candidate biomarkers for predicting therapeutic outcomes in MS and it calls for validation in larger studies, which may enhance our understanding of disease pathophysiology and offer a promising tool for personalized treatment strategies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70093","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T02:11:02Z","timestamp":1749694262000},"page":"1595-1607","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Plasma <scp>microRNA<\/scp> Signature as Predictive Marker of Clinical Response to Therapy During Multiple Sclerosis"],"prefix":"10.1002","volume":"12","author":[{"given":"Fortunata","family":"Carbone","sequence":"first","affiliation":[{"name":"Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia Consiglio Nazionale delle Ricerche (IEOMI\u2010CNR)  Napoli Italy"},{"name":"Unit\u00e0 di Neuroimmunologia IRCCS Fondazione Santa Lucia  Roma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Colamatteo","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche Universit\u00e0 di Napoli \u201cFederico II\u201d  Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Micillo","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Neurologico Mediterraneo Neuromed  Pozzilli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianmarco","family":"Abbadessa","sequence":"additional","affiliation":[{"name":"UOSD Neurologia 2, Dipartimento di Scienze Mediche e Chirurgiche Avanzate Universit\u00e0 Della Campania Luigi Vanvitelli  Napoli Italy"},{"name":"Department of Brain Sciences Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Garavelli","sequence":"additional","affiliation":[{"name":"Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia Consiglio Nazionale delle Ricerche (IEOMI\u2010CNR)  Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clorinda","family":"Fusco","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliera Universitaria \u201cFederico II\u201d  Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Russo","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliera Universitaria \u201cFederico II\u201d  Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Perna","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Clinica e Chirurgia Universit\u00e0 di Napoli \u201cFederico II\u201d  Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Garziano","sequence":"additional","affiliation":[{"name":"U.O.C. 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