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Developing novel pharmacological agents to halt acute disease progression represents a critical unmet need. 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, has emerged as a promising compound with anti-inflammatory and antioxidant properties. This study aimed to investigate the therapeutic effects and mechanisms of 4-OI in the acute experimental autoimmune neuritis (EAN) model.\u00a0Throughout the EAN disease course, clinical and electrophysiological assessments were conducted. Inflammatory infiltration and demyelination in sciatic nerves were evaluated by Hematoxylin-Eosin staining and Luxol Fast Blue staining, respectively. The inflammatory response and macrophage polarization were analyzed by quantitative polymerase chain reaction, western blot, and immunofluorescence. Bone marrow-derived macrophages (BMDMs) were used to elucidate the immunomodulatory mechanisms of 4-OI in vitro.\u00a04-OI treatment significantly improved clinical scores and attenuated neuropathological damage in EAN rats. It reduced inflammatory infiltration, M1 macrophage polarization, NLRP3 inflammasome activation, and oxidative stress in the peripheral nerves. In BMDMs, 4-OI inhibited LPS\/IFN-\u03b3-induced M1 polarization, inflammatory cytokine release, and oxidative stress. These effects were mediated by activation of the Nrf2\/HO-1 pathway, as the Nrf2 inhibitor ML385 partially reversed the protective effects of 4-OI.\u00a04-OI alleviates acute-phase EAN through its anti-inflammatory and antioxidant activities, which are largely dependent on the Nrf2\/HO-1 pathway. These preclinical findings highlight 4-OI as a promising candidate for the treatment of GBS, supporting its further translational development.<\/jats:p>","DOI":"10.1007\/s10753-025-02370-w","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T08:36:27Z","timestamp":1765960587000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Neuroprotective Effect of 4-Octyl Itaconate on Acute Period of Experimental Autoimmune Neuritis"],"prefix":"10.1007","volume":"49","author":[{"given":"Lin-Jie","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2716-3793","authenticated-orcid":false,"given":"Li","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"2370_CR1","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/s41582-019-0250-9","volume":"15","author":"Sonja E Leonhard","year":"2019","unstructured":"Leonhard, Sonja E, R. 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The animal study protocols were approved by the Institutional Animal Use and Care Committee of Tianjin Medical university general hospital (IRB2024-DW-17).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical Trial Number"}}],"article-number":"5"}}