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Although integrin receptor CD49a (\n                    <jats:italic>Itga1<\/jats:italic>\n                    gene) serves as a canonical biomarker of tissue\u2010resident immune populations, its microglial expression patterns, functions, and signaling pathways have not been elucidated. In this study, we aim to investigate the impact of CD49a in hyperactivated microglia on PD pathogenesis and elucidate downstream signaling pathways. Specifically, we demonstrate microglia\u2010enriched CD49a expression with pathologically significant upregulation particularly in microglia adopting chronically activated states. Specific\n                    <jats:italic>Itga1<\/jats:italic>\n                    knockdown attenuates microglial hyperreactivity and markedly improves motor deficits in PD mouse models. Mechanistically, transcriptomic profiling of isolated microglia from mouse substantia nigra reveals significant enrichment in neurodegeneration and inflammation pathways, with PGAM5 emerging as a central regulatory node. Conditional microglial\n                    <jats:italic>Itga1<\/jats:italic>\n                    knockdown ameliorates mitochondrial dysfunction and suppresses NLRP3 inflammasome assembly via PGAM5 downregulation, thereby preserving dopaminergic neurons from neuroinflammatory degeneration. Furthermore, the disintegrin polypeptide obtustatin specifically antagonizes microglial CD49a, suppressing microglial hyperactivation and consequent chronic neuroinflammation, and ultimately ameliorating motor deficits in PD models. Collectively, these findings establish microglial CD49a\u2010targeted therapy as a novel therapeutic paradigm for PD, positioning obtustatin as a promising clinical candidate with demonstrable translational potential across neuroinflammatory and neurodegenerative disorders.\n                  <\/jats:p>","DOI":"10.1002\/advs.202515138","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T05:40:39Z","timestamp":1767073239000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting Microglial CD49a Inhibits Neuroinflammation and Demonstrates Therapeutic Potential for Parkinson's Disease"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4674-4888","authenticated-orcid":false,"given":"Huanpeng","family":"Lu","sequence":"first","affiliation":[{"name":"Neurosurgery Center, Department of Functional Neurosurgery, The National Key Clinical Specialty, 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