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HSPA8 is a constitutively expressed molecular chaperone involved in cellular signaling and immune-inflammatory regulation, but its role in EAE-associated neuroinflammation remains unclear. In this study, we found that HSPA8 was significantly upregulated in the spinal cord tissues of EAE mice and positively correlated with disease severity. Immunofluorescence co-staining showed that HSPA8 upregulation was more prominently associated with Iba1-positive microglia\/macrophage-enriched regions than with GFAP- or NeuN-positive regions. Intrathecal knockdown of HSPA8 attenuated EAE progression, reduced inflammatory responses, and alleviated demyelination and axonal injury. In vitro, HSPA8 knockdown reduced NLRP3 inflammasome-mediated IL-1\u03b2\/IL-18 release, caspase-1 activation, GSDMD-N formation, and pyroptosis in THP-1 cells, bone marrow-derived macrophages, and BV2 microglia, and these effects were partially restored by siRNA-resistant HSPA8 rescue. Mechanistically, HSPA8 knockdown was associated with impaired NF-\u03baB-dependent priming, as reflected by reduced p65 phosphorylation, nuclear translocation, NF-\u03baB transcriptional activity, and pro-IL-1\u03b2 expression. HSPA8 is also associated with ASC, and HSPA8 knockdown impaired NLRP3\u2013ASC interaction, ASC oligomerization, and ASC speck formation during inflammasome assembly. These findings suggest that HSPA8 is functionally associated with NLRP3 inflammasome activation through both NF-\u03baB\u2011dependent priming and ASC\u2011associated assembly, thereby contributing to neuroinflammation in EAE. HSPA8 may represent a potential therapeutic target for MS-related and other inflammasome-driven neuroinflammatory disorders.<\/jats:p>","DOI":"10.1038\/s41420-026-03215-7","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T02:45:22Z","timestamp":1782269122000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of HSPA8 alleviates experimental autoimmune encephalomyelitis via dual modulation of NLRP3 inflammasome activation: suppressing both NF-\u03baB\u2013mediated priming and ASC-dependent assembly"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2169-7195","authenticated-orcid":false,"given":"Qianqian","family":"Bai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunji","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangfei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhi","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qizhi","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7920-8626","authenticated-orcid":false,"given":"Dongmei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9067-1884","authenticated-orcid":false,"given":"Hua","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"3215_CR1","doi-asserted-by":"publisher","first-page":"ITC81","DOI":"10.7326\/AITC202106150","volume":"174","author":"MJ Olek","year":"2021","unstructured":"Olek MJ. 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