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Here, we found that repulsive guidance molecule a (RGMa) was significantly upregulated in astrocytes in a mouse model of experimental autoimmune encephalomyelitis (EAE). RGMa promoted the release of key inflammatory factors such as C-C motif chemokine ligand 2 (CCL2) from astrocytes. Through protein interaction screening, we identified the E3 ubiquitin ligase, tripartite motif-containing (TRIM) protein 21 (TRIM21), as a interaction protein of RGMa. Mechanistically, TRIM21 enhanced the stability of RGMa by catalyzing K33-linked ubiquitination at lysine 238 of RGMa in vitro. Astrocyte-specific knockdown of TRIM21 decreased the expression of both RGMa and CCL2, thereby effectively alleviating neurological deficits, inflammatory infiltration, and demyelination in acute EAE. Over-expression of RGMa reversed this protective effect in primary astrocytes. Notably, Quisinostat disrupted this signaling cascade by downregulating TRIM21 and consequently attenuating RGMa-mediated CCL2 induction, at least in part through TRIM21-dependent mechanisms, thereby exhibiting therapeutic potential for acute EAE. These results suggest that TRIM21-mediated stabilization of RGMa via K33-linked ubiquitination may represent a pathway contributing to astrocyte-mediated neuroinflammation, and might offer a potential target for MS intervention.<\/jats:p>","DOI":"10.1186\/s12974-026-03769-4","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T08:47:13Z","timestamp":1773910033000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["TRIM21 promotes astrocyte-mediated neuroinflammation in experimental autoimmune encephalomyelitis by stabilizing RGMa via K33-linked ubiquitination"],"prefix":"10.1186","volume":"23","author":[{"given":"Shaoru","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqi","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"3769_CR1","doi-asserted-by":"publisher","first-page":"eadq1177","DOI":"10.1126\/science.adq1177","volume":"390","author":"Y Li","year":"2025","unstructured":"Li Y, Li Z, Zheng P, Guan S, Li Y, Yao N, Qi Z, Zhang X, Su L, Jing J, et al. 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