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Through re\u2010analysis of single\u2010cell RNA sequencing data from AUD patients, we identified aberrant activation of lipid metabolic pathways in microglia and pinpointed acyl\u2010CoA synthetase long\u2010chain family member 1 (ACSL1) as a central regulator. In animal and cellular models, chronic ethanol exposure induced ACSL1 upregulation, triggering lipid droplet accumulation, neuroinflammatory activation, and aberrant microglia\u2013neuron interactions mediated via PTPRM signaling. Pharmacological inhibition of ACSL1 reversed these pathological phenotypes. We further developed a dual\u2010targeted lipid nanoparticle system for microglia\u2010specific ACSL1 silencing, which effectively ameliorated ethanol\u2010induced cognitive deficits in mice. 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