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However, the underlying pathological mechanisms remain largely unclear. Lipid\u2010droplet\u2010accumulating microglia\u00a0(LDAM) have been linked to age\u2010related and genetic forms\u00a0of\u00a0neurodegeneration, prompting the investigation of their role in hypoxia\u2010induced neuronal impairment. In this study, we observed that hypoxia induced lipid droplets accumulation in microglia, accompanied by increased levels of RETSAT, an enzyme involved in lipid metabolism regulation. Conditional knockout of RETSAT in microglia decreased lipid droplets\u00a0accumulation and alleviates hypoxia\u2010induced microglial\u2010derived neuroinflammation and oxidative stress, both in\u00a0vitro and in\u00a0vivo. Our biological studies indicate that the beneficial effects of RETSAT knockout on lipid droplets degradation are\u00a0primarily mediated through enhanced activity of hormone\u2010sensitive lipase (HSL). Furthermore, we found that the hypoxic\u00a0adaptation\u2010related RETSAT mutation Q247R promotes microglia lipolysis under hypoxic conditions. These findings suggest that RetSat is a potential therapeutic target for the prevention and treatment of hypoxia\u2010induced microglial activation.<\/jats:p>","DOI":"10.1002\/glia.70118","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T07:40:14Z","timestamp":1765611614000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>RetSat<\/scp>\n                    Knockout Mitigates Hypoxia\u2010Induced Microglial Activation by Enhancing Lipid Droplets Degradation"],"prefix":"10.1002","volume":"74","author":[{"given":"Wenyu","family":"Hu","sequence":"first","affiliation":[{"name":"The Brain Science Center, Beijing Institute of Basic Medical Sciences  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3499-2717","authenticated-orcid":false,"given":"Shuoshuo","family":"Li","sequence":"additional","affiliation":[{"name":"The 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