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However, the underlying mechanisms linking hepatic metabolic dysfunction to neurodegeneration remain unclear. In this study, we systematically investigated the liver\u2013brain axis by integrating genetic epidemiology, experimental neuroscience, and transcriptomics techniques. Two\u2010sample Mendelian randomization (MR) analysis revealed a potential causal relationship between MASLD and cognitive decline. These findings were validated in a high\u2010fat diet (HFD)\u2013induced MASLD mouse model, which exhibited hallmark features of metabolic dysfunction, including significant body fat accumulation and elevated serum levels of pro\u2010inflammatory cytokines (interleukin\u20106 [IL\u20106] and tumor necrosis factor\u2010\u03b1[TNF\u2010\u03b1]). Behavioral assays demonstrated pronounced anxiety\u2010like behaviors and impaired spatial memory. Neuropathological analysis revealed neuronal loss and structural alterations in the hippocampal dentate gyrus (DG), accompanied by astrocyte remodeling and M1 microglial polarization, indicating neuroinflammation\u2010driven disruption of hippocampal circuits. At the molecular level, MASLD altered the expression of key hippocampal genes\u2014including\n                    <jats:italic>TCF7L2<\/jats:italic>\n                    ,\n                    <jats:italic>LCN2<\/jats:italic>\n                    , and\n                    <jats:italic>AQP1<\/jats:italic>\n                    \u2014impacting immune response, lipid metabolism, and apoptotic pathways, which collectively contributed to cognitive deficits. Dual immunofluorescence staining, combined with Sholl and 3D analysis quantitatively characterized neuroglial morphological and functional changes, providing structural\u2010level evidence for MASLD\u2013related brain dysfunction. Taken together, our findings identify MASLD as a modifiable risk factor for neurodegeneration, with systemic inflammation playing a pivotal role in the liver\u2013brain axis. This study highlights key genes and pathways underlying MASLD\u2013induced cognitive impairment, advances understanding of metabolic\u2010neural cross talk, and offers potential therapeutic targets for mitigating cognitive decline through intervention in the liver\u2013brain axis, developing intervention strategies and highlight the therapeutic promise of targeting the liver\u2013brain axis.\n                  <\/jats:p>","DOI":"10.1155\/mi\/5555342","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T07:34:24Z","timestamp":1770708864000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inflammatory Factors Derived From Metabolic Dysfunction\u2010Alcoholic Fatty Liver Disease: Inducers of Anxiety and Spatial Memory 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