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Increasing evidence links microglial activation and lipid metabolism dysregulation to neurodegeneration.\u00a0However, the role of microglial lipid metabolic reprogramming in disease pathogenesis remains unclear.\u00a0This study finds that microglia in an acute ocular hypertension (AOH) model exhibit abnormal lipid droplet accumulation, downregulation of low\u2010density lipoprotein receptor\u2010related protein 1 (LRP1), and a shift toward a pro\u2010inflammatory M1 phenotype.\u00a0Importantly, serum samples from glaucoma patients reveal significantly reduced LRP1 levels compared to controls. To restore lipid homeostasis, this study develops alpinetin\u2010loaded PLGA nanoparticles (AlpNPs), which demonstrate efficient microglial uptake and sustained release. AlpNPs reduced intracellular lipid accumulation, promoted M2 polarization, and suppressed microglial proliferation and migration. Mechanistically, AlpNPs directly bind to LRP1 and enhance its interaction with PPAR\u03b3,\u00a0thereby activating the downstream LXR\u03b1\u2010ABCA1 pathway, which is pivotal for cholesterol efflux and anti\u2010inflammatory responses. Knockdown of LRP1 abolished the protective effects of AlpNPs, confirming its essential role in mediating metabolic reprogramming. In vivo, intravitreal injection of AlpNPs significantly attenuates retinal inflammation and preserves RGCs in AOH. These findings identify microglial lipid metabolic dysfunction as a key driver in glaucoma and highlight LRP1\u2010targeted nanotherapy as a promising strategy for neuroprotection.<\/jats:p>","DOI":"10.1002\/advs.202513270","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T08:01:11Z","timestamp":1762934471000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Alpinetin Nanoparticles Alleviate Optic Nerve Injury Induced by Acute Glaucoma via LRP1\u2010PPAR\u03b3 Mediated Regulation of Microglial Lipid Metabolism"],"prefix":"10.1002","volume":"13","author":[{"given":"Miao","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Ophthalmology The First Affiliated Hospital of Chongqing Medical University  Chongqing P. R. 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