Abstract
Abnormal astrocytes activation contributes to disease progression in multiple sclerosis (MS), yet the regulatory mechanisms are not fully understood. 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03769-4.