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Previous research has indicated a role for DNA methylation in sepsis. However, its involvement in SAE remains underexplored. In this study, a sepsis model was established in adult male C57BL\/6J mice through intraperitoneal injection of lipopolysaccharide (LPS) at a dose of 5\u2009mg\/kg to explore the relationship between DNA methylation and spatial memory impairment associated with SAE. Following LPS administration, the mice exhibited impaired learning and spatial memory. RNA sequencing of hippocampal tissues from SAE mouse models revealed differential gene expression, with 797 upregulated and 510 downregulated genes in the hippocampus 24\u2009h post\u2010LPS administration. Both GO and KEGG analyses indicated an enrichment of inflammation\u2010related pathways. MeDIP\u2010seq of the hippocampus identified 1628 hyper\u2010methylated and 2245 hypo\u2010methylated genes, with the latter being primarily enriched in synapse\u2010related pathways. Seventy\u2010one genes exhibited transcription trends opposite to their 5mC levels. RT\u2010qPCR was used to validate the mRNA expression and methylation patterns of six genes, revealing that\n                    <jats:italic>Apmap<\/jats:italic>\n                    exhibited reduced promoter region methylation, accompanied by increased mRNA expression, while its overexpression alleviated these deficits. These findings suggest that\n                    <jats:italic>Apmap<\/jats:italic>\n                    may play a protective role in spatial memory impairment in SAE. The results present promising epigenetic biomarkers for early clinical diagnosis and potential therapeutic targets in SAE.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70120-fig-0010-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70120","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T08:46:18Z","timestamp":1750149978000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative Analysis of DNA Methylation and Gene Expression Reveals Key Molecular Signatures in Spatial Memory Impairment of Sepsis\u2010Associated Encephalopathy"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8140-9261","authenticated-orcid":false,"given":"Xin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Zhongnan Hospital of Wuhan University  Wuhan China"},{"name":"Brain Research Center Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiazhi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Brain Research Center Zhongnan Hospital of Wuhan University  Wuhan China"},{"name":"Department of Neurosurgery Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bofu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Zhongnan Hospital of Wuhan University  Wuhan 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