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Mangiferin (MGF), a natural flavonoid compound, has been suggested in previous reports to have potential in the treatment of AD. This study integrated network pharmacology and in\u00a0vivo experiments to elucidate the therapeutic potential and mechanisms of MGF in mitigating FA\u2010induced neurotoxicity. Potential overlapping targets between MGF and AD were identified using jvenn. Functional enrichment analysis of these targets was performed with DAVID. A protein\u2013protein interaction (PPI) network was constructed using STRING and visualized in Cytoscape to identify hub genes. Molecular docking simulations with AutoDock were then employed to assess binding affinity. Subsequently, for experimental validation, a mouse model of FA\u2010induced neurotoxicity was established. Spatial memory and cognitive function in mice were evaluated using the Y\u2010maze and novel object recognition tests. The expression levels of key pathway\u2010related proteins in the cortex and hippocampus were analyzed via immunohistochemistry (IHC) and Western blotting (WB). Network analysis identified AKT1 and GSK3\u03b2 as key targets, and molecular docking confirmed strong binding affinity between MGF and these proteins. Experimental validation demonstrated that MGF dose\u2010dependently improved spatial memory and cognitive performance in FA\u2010exposed mice, reduced neuronal apoptosis, and suppressed Tau hyperphosphorylation at Thr181, Ser396, and Ser404. Mechanistically, MGF activated the PI3K\/AKT pathway, leading to GSK3\u03b2 inactivation through Ser9 phosphorylation. These findings highlight MGF as a promising therapeutic candidate for AD by targeting the PI3K\/AKT\/GSK3\u03b2 axis.<\/jats:p>","DOI":"10.1096\/fj.202503159r","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T15:11:07Z","timestamp":1768489867000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mangiferin Alleviates Formaldehyde\u2010Induced Tau Hyperphosphorylation and Cognitive Impairment in Mice via the PI3K\/AKT\/GSK3\u03b2 Pathway: Insights From Network Pharmacology and Experimental Validation"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1797-574X","authenticated-orcid":false,"given":"Na","family":"Wang","sequence":"first","affiliation":[{"name":"Laboratory of Brain and Cognitive Science, School of Basic Medical Sciences Dali University  Dali Yunnan China"},{"name":"School of Medical Laboratory Northern Henan Medical University  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