{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:22:06Z","timestamp":1790126526212,"version":"4.0.1"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Inflammation and oxidative stress contribute significantly to tissue damage in multiple sclerosis. Fumaric acid esters such as Dimethyl fumarate and Diroximel fumarate (DRF) exhibit immunomodulatory and antioxidative properties, although their mechanisms remain incompletely understood. This study investigated the immunomodulatory and antioxidative mechanisms of fumaric acid esters, with a focus on DRF and its ability to confer neuroprotection in autoimmune neuroinflammation. The MOG-experimental autoimmune encephalomyelitis (EAE) mouse model was employed and DRF was administered orally. In addition to clinical scoring of EAE severity, histological analyses were performed to assess inflammatory infiltration, demyelination, and axonal density. Immune responses were examined via immunophenotyping and cytokine measurements, and mRNA expression was analyzed to evaluate Nrf2 pathway activation. DRF treatment markedly ameliorated clinical EAE severity, reduced spinal cord infiltration of T cells\u2014particularly Th1 cells\u2014and promoted myelin and axonal preservation. Peripheral immune cells from DRF-treated mice produced lower levels of IFN-\u03b3 and IL-17A, while Nrf2-dependent antioxidative genes were upregulated in CNS tissue. Our results demonstrate neuroprotective, immunomodulatory, and antioxidative effects of DRF, supporting its role as beneficial modulator in neuroinflammation.<\/jats:p>","DOI":"10.1371\/journal.pone.0355936","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T17:24:18Z","timestamp":1786987458000},"page":"e0355936","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diroximel fumarate confers neuroprotection via reduced Th1 responses and induction of the anti-oxidative Nrf2 pathway in experimental neuroinflammation"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6641-9568","authenticated-orcid":true,"given":"David","family":"Freudenstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Schneeweiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Krenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Gold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Linker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Haase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"pone.0355936.ref001","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s40263-022-00939-9","article-title":"Efficacy and safety of multiple sclerosis drugs approved since 2018 and future developments","volume":"36","author":"S Faissner","year":"2022","journal-title":"CNS Drugs"},{"issue":"1","key":"pone.0355936.ref002","article-title":"Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis","volume":"1","author":"M Gonzalez-Lorenzo","year":"2024","journal-title":"Cochrane Database Syst Rev"},{"key":"pone.0355936.ref003","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1007\/s12325-022-02068-7","article-title":"Efficacy and safety outcomes with diroximel fumarate after switching from prior therapies or continuing on DRF: results from the phase 3 EVOLVE-MS-1 study","volume":"39","author":"S Wray","year":"2022","journal-title":"Adv Ther"},{"issue":"2","key":"pone.0355936.ref004","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s40263-020-00700-0","article-title":"Diroximel fumarate demonstrates an improved gastrointestinal tolerability profile compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: results from the randomized, double-blind, phase III EVOLVE-MS-2 Study","volume":"34","author":"RT Naismith","year":"2020","journal-title":"CNS Drugs"},{"issue":"3","key":"pone.0355936.ref005","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0120254","article-title":"Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro","volume":"10","author":"MS Brennan","year":"2015","journal-title":"PLoS One"},{"issue":"6","key":"pone.0355936.ref006","doi-asserted-by":"crossref","first-page":"13885","DOI":"10.3390\/ijms160613885","article-title":"Dimethyl fumarate protects neural stem\/progenitor cells and neurons from oxidative damage through Nrf2-ERK1\/2 MAPK pathway","volume":"16","author":"Q Wang","year":"2015","journal-title":"Int J Mol Sci"},{"key":"pone.0355936.ref007","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1093\/brain\/awq386","article-title":"Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway","volume":"134","author":"RA Linker","year":"2011","journal-title":"Brain"},{"issue":"1","key":"pone.0355936.ref008","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1124\/jpet.111.190132","article-title":"Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway","volume":"341","author":"RH Scannevin","year":"2012","journal-title":"J Pharmacol Exp Ther"},{"key":"pone.0355936.ref009","doi-asserted-by":"crossref","first-page":"1209923","DOI":"10.3389\/fimmu.2023.1209923","article-title":"Dimethyl fumarate-related immune and transcriptional signature is associated with clinical response in multiple sclerosis-treated patients","volume":"14","author":"A S\u00e1nchez-Sanz","year":"2023","journal-title":"Front Immunol"},{"issue":"17","key":"pone.0355936.ref010","doi-asserted-by":"crossref","first-page":"4777","DOI":"10.1073\/pnas.1603907113","article-title":"Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2","volume":"113","author":"U Schulze-Topphoff","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0355936.ref011","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jaut.2017.09.009","article-title":"Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis","volume":"86","author":"M Diebold","year":"2018","journal-title":"J Autoimmun"},{"key":"pone.0355936.ref012","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jneuroim.2015.04.006","article-title":"DMF, but not other fumarates, inhibits NF-\u03baB activity in vitro in an Nrf2-independent manner","volume":"283","author":"GO Gillard","year":"2015","journal-title":"J Neuroimmunol"},{"issue":"5","key":"pone.0355936.ref013","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1172\/JCI72151","article-title":"Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate\u2019s protective effect in EAE","volume":"124","author":"H Chen","year":"2014","journal-title":"J Clin Invest"},{"key":"pone.0355936.ref014","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.msard.2018.04.016","article-title":"Dimethyl fumarate downregulates the immune response through the HCA2\/GPR109A pathway: implications for the treatment of multiple sclerosis","volume":"23","author":"F von Glehn","year":"2018","journal-title":"Mult Scler Relat Disord"},{"key":"pone.0355936.ref015","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jneuroim.2016.08.006","article-title":"Dimethyl fumarate alters microglia phenotype and protects neurons against proinflammatory toxic microenvironments","volume":"299","author":"H Peng","year":"2016","journal-title":"J Neuroimmunol"},{"issue":"7","key":"pone.0355936.ref016","doi-asserted-by":"crossref","first-page":"630","DOI":"10.3390\/antiox9070630","article-title":"Antioxidant and anti-inflammatory effect of Nrf2 inducer dimethyl fumarate in neurodegenerative diseases","volume":"9","author":"SA Scuderi","year":"2020","journal-title":"Antioxidants (Basel)"},{"issue":"445","key":"pone.0355936.ref017","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.aaf7694","article-title":"Chemical proteomic map of dimethyl fumarate-sensitive cysteines in primary human T cells","volume":"9","author":"MM Blewett","year":"2016","journal-title":"Sci Signal"},{"issue":"1","key":"pone.0355936.ref018","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/acn3.270","article-title":"Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis","volume":"3","author":"MA Michell-Robinson","year":"2015","journal-title":"Ann Clin Transl Neurol"},{"issue":"7","key":"pone.0355936.ref019","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"J Schindelin","year":"2012","journal-title":"Nat Methods"},{"issue":"2","key":"pone.0355936.ref020","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1177\/135245859800400203","article-title":"Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions","volume":"4","author":"I Mews","year":"1998","journal-title":"Mult Scler"},{"key":"pone.0355936.ref021","doi-asserted-by":"crossref","first-page":"116054","DOI":"10.1016\/j.intimp.2025.116054","article-title":"Effect of diroximel fumarate on gut dysbiosis and autoimmunity in the central nervous system","volume":"169","author":"SK Yadav","year":"2026","journal-title":"Int Immunopharmacol"},{"key":"pone.0355936.ref022","doi-asserted-by":"crossref","first-page":"101451","DOI":"10.1016\/j.msard.2019.101451","article-title":"Dimethyl fumarate therapy reduces memory T cells and the CNS migration potential in patients with multiple sclerosis","volume":"37","author":"R Holm Hansen","year":"2020","journal-title":"Mult Scler Relat Disord"},{"key":"pone.0355936.ref023","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.4049\/jimmunol.1601532","article-title":"Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1\/Th17 and Th2 in multiple sclerosis patients","volume":"198","author":"Q Wu","year":"2017","journal-title":"J Immunol"},{"issue":"1","key":"pone.0355936.ref024","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1111\/j.1365-2249.2006.03094.x","article-title":"Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration","volume":"145","author":"S Schilling","year":"2006","journal-title":"Clin Exp Immunol"},{"issue":"1","key":"pone.0355936.ref025","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13550-022-00878-y","article-title":"Dimethyl fumarate decreases short-term but not long-term inflammation in a focal EAE model of neuroinflammation","volume":"12","author":"SK Vainio","year":"2022","journal-title":"EJNMMI Res"},{"key":"pone.0355936.ref026","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.expneurol.2015.02.022","article-title":"Dimethyl fumarate attenuates cerebral edema formation by protecting the blood-brain barrier integrity","volume":"266","author":"R Kunze","year":"2015","journal-title":"Exp Neurol"},{"key":"pone.0355936.ref027","doi-asserted-by":"crossref","first-page":"114572","DOI":"10.1016\/j.expneurol.2023.114572","article-title":"Assessing neuroprotective effects of diroximel fumarate and siponimod via modulation of pacemaker channels in an experimental model of remyelination","volume":"371","author":"L Vinnenberg","year":"2024","journal-title":"Exp Neurol"},{"key":"pone.0355936.ref028","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.redox.2018.08.014","article-title":"Identification of a functional antioxidant response element at the HIF1A locus","volume":"19","author":"SE Lacher","year":"2018","journal-title":"Redox Biol"},{"issue":"130","key":"pone.0355936.ref029","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2000762","article-title":"Regulation of notch1 signaling by nrf2: implications for tissue regeneration","volume":"3","author":"N Wakabayashi","year":"2010","journal-title":"Sci Signal"},{"issue":"20","key":"pone.0355936.ref030","doi-asserted-by":"crossref","first-page":"7188","DOI":"10.1128\/MCB.00915-07","article-title":"NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis","volume":"27","author":"S Shin","year":"2007","journal-title":"Mol Cell Biol"},{"issue":"50","key":"pone.0355936.ref031","doi-asserted-by":"crossref","first-page":"36412","DOI":"10.1074\/jbc.M706517200","article-title":"An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance","volume":"282","author":"O-H Lee","year":"2007","journal-title":"J Biol Chem"},{"key":"pone.0355936.ref032","doi-asserted-by":"crossref","first-page":"116675","DOI":"10.1016\/j.intimp.2026.116675","article-title":"Dimethyl fumarate alleviates oxidative stress and inflammation in noise-induced hearing loss by activating Nrf2\/HO-1 signaling in cochlear hair cells","volume":"180","author":"M Li","year":"2026","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"pone.0355936.ref033","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s12974-025-03592-3","article-title":"Fumarate-based drugs protect against neuroinflammation via upregulation of anti-ferroptotic pathways","volume":"22","author":"K Fischer","year":"2025","journal-title":"J Neuroinflammation"},{"issue":"5","key":"pone.0355936.ref034","first-page":"827","article-title":"Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decrease ISR activation in DRG neurons","volume":"74","author":"MS Yousuf","year":"2025","journal-title":"Diabetes"},{"issue":"4","key":"pone.0355936.ref035","doi-asserted-by":"crossref","DOI":"10.1212\/NXI.0000000000000470","article-title":"Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS","volume":"5","author":"AR Gafson","year":"2018","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"issue":"10","key":"pone.0355936.ref036","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1093\/brain\/awab307","article-title":"Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity","volume":"144","author":"M Liebmann","year":"2021","journal-title":"Brain"},{"issue":"22","key":"pone.0355936.ref037","doi-asserted-by":"crossref","first-page":"15244","DOI":"10.1074\/jbc.M113.540633","article-title":"Transcription factors NRF2 and NF-\u03baB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation","volume":"289","author":"A Cuadrado","year":"2014","journal-title":"J Biol Chem"},{"issue":"7","key":"pone.0355936.ref038","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1074\/jbc.M115.679704","article-title":"Dimethyl fumarate inhibits the nuclear factor \u03baB pathway in breast cancer cells by covalent modification of p65 protein","volume":"291","author":"I Kastrati","year":"2016","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0355936.ref039","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/ncb2699","article-title":"Nrf2 regulates haematopoietic stem cell function","volume":"15","author":"JJ Tsai","year":"2013","journal-title":"Nat Cell Biol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0355936","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T17:24:24Z","timestamp":1786987464000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0355936"}},"subtitle":[],"editor":[{"given":"Orhan","family":"Aktas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0355936","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]}}}