{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:02:10Z","timestamp":1792458130582,"version":"4.5.0"},"reference-count":49,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82525023"],"award-info":[{"award-number":["82525023"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["W2411087"],"award-info":[{"award-number":["W2411087"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U22A20295"],"award-info":[{"award-number":["U22A20295"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["25X010202804"],"award-info":[{"award-number":["25X010202804"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2025M782150"],"award-info":[{"award-number":["2025M782150"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Cerebral ischemic stroke triggers extensive neuronal membrane breakdown, releasing a massive load of cholesterol that overwhelms resident microglia. Dysregulated microglial cholesterol metabolism has been implicated in post\u2010stroke neuroinflammation, yet the specific pathogenic microglial subpopulations, their molecular signatures, and the downstream inflammatory cascades remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed a permanent distal middle cerebral artery occlusion (dMCAO) model combined with single\u2010cell RNA sequencing (scRNA\u2010seq) to profile immune cell transcriptomes and identify cholesterol\u2010associated microglial markers. Cholesterol dynamics, lipid droplet accumulation, and inflammatory marker expression were quantified via immunofluorescence and transmission electron microscopy. Therapeutic interventions included pharmacological cholesterol mobilization with 2\u2010hydroxypropyl\u2010\u03b2\u2010cyclodextrin (H\u03b2CD), pharmacological STING inhibition with C\u2010176, and microglia\u2010targeted STING knockdown using AAV9 vectors. Cerebral injury and neurological function were assessed through infarct volume measurement, white matter integrity analysis, and behavioral assays (rotarod and grip strength) in dMCAO, tMCAO, and perioperative stroke (PIS) models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Using scRNA\u2010seq, we identified interferon\u2010induced transmembrane protein 3 (IFITM3) as a specific marker for a microglial subpopulation that was characterized by upregulated ACAT1, enhanced cholesterol esterification, and accumulation of cholesterol crystals and lipid droplets. This IFITM3\n                      <jats:sup>+<\/jats:sup>\n                      microglia population peaked at 7\u2009days post\u2010stroke and correlated with NLRP3 inflammasome activation and STING signaling. Pharmacological reduction of cholesterol burden with H\u03b2CD attenuated lipid droplet formation, suppressed mitochondrial DNA leakage, and inhibited STING pathway activation. Correspondingly, H\u03b2CD and C\u2010176 administration significantly reduced cerebral infarct size, mitigated white matter demyelination, and improved motor function in dMCAO and tMCAO models. We further found that AAV\u2010mediated STING knockdown recapitulated the above protective effects in H\u03b2CD and C\u2010176 treated stroke mice. Furthermore, H\u03b2CD treatment ameliorated microglial inflammation and improved functional outcomes in a PIS model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      IFITM3\n                      <jats:sup>+<\/jats:sup>\n                      microglia is a pro\u2010inflammatory and cholesterol\u2010laden subpopulation that exacerbates post\u2010stroke cerebral ischemic brain injury. Targeting the microglial cholesterol axis by H\u03b2CD or inhibiting the STING pathway represents a promising therapeutic strategy to mitigate ischemic brain injury and improve neurological function.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.71073","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T10:11:16Z","timestamp":1786443076000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cholesterol Drives\n                    <scp>IFITM3<\/scp>\n                    <sup>+<\/sup>\n                    Microglia Activation and Induces\n                    <scp>STING<\/scp>\n                    Mediated Neuroinflammation After Ischemic Stroke"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9169-7707","authenticated-orcid":false,"given":"Yue","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Key Laboratory of Anesthesiology Shanghai Jiao Tong University, Ministry of Education  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5641-235X","authenticated-orcid":false,"given":"Yuxi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Key Laboratory of Anesthesiology Shanghai Jiao Tong University, Ministry of Education  Shanghai 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