GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE331nnn/GSE331058/primary200OKTranscriptomicsRattus norvegicusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331058GEOGSEfalseThe GPR17 agonist galinex restores oligodendrocyte maturation under inflammatory conditionsChronic neuroinflammation disrupts oligodendrocyte differentiation and limits effective remyelination across multiple neurological disorders. Among the molecular regulators integrating inflammatory cues with oligodendrocyte maturation, G protein-coupled receptor 17 (GPR17) has emerged as a critical checkpoint. Physiologically, GPR17 expression is low in early oligodendrocyte precursors (OPCs) and peaks in immature oligodendrocytes, after which it must be downregulated to allow cells’ terminal maturation. Under neuroinflammatory conditions, GPR17 is permanently upregulated, suggesting a role in blockade of oligodendrocyte (OL) maturation and in defective myelination. Here, we tested whether receptor modulation by the specific agonist Galinex (GAL) can restore proper OL maturation under neuroinflammatory conditions. We first showed that subtoxic inflammatory stress, defined as cytokine exposure that did not cause overt loss of cell viability, consistently impaired oligodendrocyte morphological maturation, reduced the expression of myelin-associated markers, and was accompanied by increased GPR17 expression. Transcriptomics analysis revealed that CTK (Cytokines) induced coordinated transcriptional remodelling involving protein synthesis/proteostasis, mitochondrial metabolism, and lipid-related pathways, together with a shift towards an immunogenic-like, senescence/DNA-damage–associated phenotype. Cross-comparison with publicly available transcriptomic signatures of neuroinflammatory patterns from both mouse models and Alzheimer’s and multiple sclerosis human brains, revealed significant overlap with disease-associated modules, supporting the relevance of the inflammatory pathways engaged in our model. We then showed that treatment of OLs with GAL restored cells’ terminal maturation and morphological features. Moreover, in a synthetic nanofiber myelination assay, GAL significantly increased the length of myelinated segments compared to CTK-treated cells, suggesting an improvement of OL myelinating capacity after inflammatory damage. Together, this study establishes a controlled in vitro model linking alteration of disease-relevant transcriptional pathways to impaired OL differentiation and highlights GPR17 pharmacological modulation as a feasible strategy to promote OL maturation under non permissive inflammatory contexts.2026/06/25GSE331058GSM9738289GSM9738288GSM9738298GSM9738287GSM9738297GSM9738296GSM9738295GSM9738294GSM9738293GSM9738292GSM9738291GSM973829034877331058Rattus norvegicus[42328628]