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This study identifies the lncRNA ZEB1\u2010AS1 as a central coordinator of microglial immunity against Spn through a multi\u2010tiered regulatory cascade. Transcriptomic analysis revealed Spn\u2010induced ZEB1\u2010AS1 upregulation in human microglia, driven by ZNF148, which directly binds its promoter. Functional interrogation demonstrated that ZEB1\u2010AS1 knockdown impairs bacterial clearance and pro\u2010inflammatory cytokine production (IL\u20101\u03b2, IL\u20106, TNF\u2010\u03b1,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01), while its overexpression amplifies these responses. Crucially, ZEB1\u2010AS1 recruits the m6A reader IGF2BP2 to stabilize NOD2 mRNA in cytoplasmic complexes, extending transcript stability. This molecular scaffolding enables NOD2\u2010dependent antimicrobial functions, as evidenced by rescue experiments in which IGF2BP2 overexpression reversed ZEB1\u2010AS1 deficiency phenotypes. In\u00a0vivo, microglial manipulation of the murine homolog Zeb1\u2010os1 regulated cerebral Spn burdens, NOD2 expression, and infection\u2010induced cognitive outcomes in both directions. The tripartite ZEB1\u2010AS1\/IGF2BP2\/NOD2 interaction was validated by RNA pulldown and co\u2010immunoprecipitation, establishing a linear pathway from ZNF148\u2010mediated transcriptional activation to IGF2BP2\u2010dependent mRNA stabilization. Collectively, this ZNF148 to ZEB1\u2010AS1 to IGF2BP2 to NOD2 axis bridges the gap between transcriptional and post\u2010transcriptional immune regulation, proposing IGF2BP2's RNA\u2010binding domain as a therapeutic target against drug\u2010resistant Spn meningitis.\n                  <\/jats:p>","DOI":"10.1002\/glia.70125","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T03:52:59Z","timestamp":1766980379000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The\n                    <scp>ZNF148<\/scp>\n                    \u2010\n                    <scp>ZEB1<\/scp>\n                    \u2010\n                    <scp>AS1<\/scp>\n                    \u2010\n                    <scp>IGF2BP2<\/scp>\n                    \u2010\n                    <scp>NOD2<\/scp>\n                    Axis Drives Microglial Antipneumococcal Immunity in Bacterial Meningitis"],"prefix":"10.1002","volume":"74","author":[{"given":"Xiufu","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Pediatrics Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinjie","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Public Health Clinical Center  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruimei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of 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