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This study investigates the neuroprotective potential of orlistat (ORL), a gastrointestinal lipase inhibitor, in a murine TBI model. Behavioral, histological, and molecular analyses demonstrated that ORL significantly attenuated TBI-induced neurological damage. Microglial depletion experiments revealed that ORL\u2019s neuroprotective effects were largely mediated through microglial modulation. In vitro and in vivo studies showed that ORL suppressed microglial activation, phagocytosis, and migration. Single-cell RNA sequencing identified upregulation of lipoprotein lipase (LPL) in a TBI-induced microglial subpopulation. Molecular docking predicted ORL-LPL binding, suggesting direct enzymatic inhibition. Transcriptomic and metabolomic analyses further revealed ORL\u2019s modulation of microglial metabolic pathways and inflammatory responses. Our findings position ORL as a promising repurposed therapeutic for TBI through its novel mechanism of targeting microglial LPL-mediated neuroinflammation.<\/jats:p>","DOI":"10.3390\/cells14181469","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T16:53:42Z","timestamp":1758300822000},"page":"1469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Orlistat Confers Neuroprotection in Traumatic Brain Injury by Modulating Microglial Lipid Metabolism"],"prefix":"10.3390","volume":"14","author":[{"given":"Chenxuan","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China"},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, 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