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Currently, immunomodulatory therapies for MS have very limited effects on disease progression and long\u2010term prognosis. Therefore, pro\u2010myelinating strategy has been attracting more and more attention. Astrocyte reactivation has been reported in many demyelination conditions and is supposed to play a duplex effect during demyelination and remyelination, while the detailed underlying mechanism remains unknown. Here, we report that reactive astrocytes in cuprizone\u2010induced demyelination mice showed sustained upregulation of the expression of P2 purinergic receptor X1 (P2X1). Pharmacologic blockade of P2X1 receptor signaling by receptor\u2010specific antagonist NF449 significantly enhanced\/accelerated remyelination and altered new OL production dynamics. Furthermore, astrocyte\u2010specific conditional knockout of the\n                    <jats:italic>P2X1<\/jats:italic>\n                    gene promoted remyelination and led to early onset of new OL production. In addition, conditioned medium (CM) from ATP treated astrocyte culture that overexpressed\n                    <jats:italic>P2X1<\/jats:italic>\n                    significantly hindered the differentiation of oligodendrocyte precursor cells (OPCs) in\u00a0vitro compared to CM from empty vector virus\u2010infected astrocytes with the same treatment, suggesting the secretion of certain inhibitory factors for OPC maturation and myelination by astrocytes with upregulated P2X1 receptor expression. Taken together, our study indicates that abnormal P2X1 receptor signaling in reactive astrocytes may be an important endogenous inhibitory factor for remyelination, and blockade of this pathway might be a potential target for pro\u2010myelination therapy strategy for demyelinating diseases.\n                  <\/jats:p>","DOI":"10.1002\/glia.70121","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T13:00:57Z","timestamp":1766149257000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing Remyelination by Blockade of Astrocytic\n                    <scp>P2X1<\/scp>\n                    Receptors Signaling in Cuprizone\u2010Induced Demyelination Mouse Model"],"prefix":"10.1002","volume":"74","author":[{"given":"Zhengtao","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences of Ministry of Education; Institute for 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