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Our previous multi\u2010omics data revealed significant upregulation of leukocyte immunoglobulin\u2010like receptor subfamily B member 4 (LILRB4) in microglia after transient middle cerebral artery occlusion (tMCAO), but its functional role remains unclear. This study demonstrates that LILRB4 expression peaks at 3\u2009days post\u2010tMCAO and is predominantly localized to microglia. Microglia\u2010specific\n                    <jats:italic>Lilrb4<\/jats:italic>\n                    knockout (\n                    <jats:italic>Lilrb4<\/jats:italic>\n                    \u2010cKO) displayed worse neurological functions, larger infarct volumes, and more significant microglial activation. Transcriptomic analysis in\u00a0vitro and functional experiments further revealed that microglial LILRB4 knockdown promoted the release of proinflammatory factors and enhanced necroptosis. Mechanistically, deletion of LILRB4 mainly drives receptor\u2010interacting protein 3 (RIPK3) and mixed lineage kinase domain\u2010like (MLKL) expression and phosphorylation, without affecting receptor\u2010interacting protein 1 (RIPK1). Pharmacologic inhibition of RIPK3 can relieve the brain damage caused by LILRB4 knockout after stroke. Additional analysis showed that LILRB4 negatively regulates the stimulator of interferon genes (STING)\/RIPK3 axis to limit microglial necroptosis. STING suppression blocked the hyperactivation of RIPK3 induced by LILRB4 deficiency. In conclusion, LILRB4 attenuates ischemic brain injury by suppressing STING\/RIPK3\u2010mediated microglial necroptosis and neuroinflammation, emphasizing its significance as a potential neuroprotective therapy.\n                  <\/jats:p>","DOI":"10.1002\/glia.70215","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T14:43:46Z","timestamp":1788273826000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>LILRB4<\/scp>\n                    Attenuates Ischemic Brain Injury by Inhibiting Microglial Necroptosis via a\n                    <scp>RIPK3<\/scp>\n                    \u2010Dependent Mechanism"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5030-2726","authenticated-orcid":false,"given":"Jinglong","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Neurology Nanjing Drum Tower Hospital, Affiliated Hospital of 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School of Nanjing University  Nanjing China"},{"name":"Nanjing Neurology Clinical Medical Center  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4459-0025","authenticated-orcid":false,"given":"Hailan","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Neurology Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University  Nanjing China"},{"name":"State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases Nanjing University  Nanjing China"},{"name":"Jiangsu Key Laboratory for Molecular Medicine Medical School of Nanjing University  Nanjing China"},{"name":"Nanjing Neurology Clinical Medical Center  Nanjing 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