Inflammatory Factors Derived From Metabolic Dysfunction-Alcoholic Fatty Liver Disease: Inducers of Anxiety and Spatial Memory Impairment

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global epidemic, with growing evidence suggesting its adverse impact on brain function. However, the underlying mechanisms linking hepatic metabolic dysfunction to neurodegeneration remain unclear. In this study, we systematically investigated the liver–brain axis by integrating genetic epidemiology, experimental neuroscience, and transcriptomics techniques. Two-sample Mendelian randomization (MR) analysis revealed a potential causal relationship between MASLD and cognitive decline. These findings were validated in a high-fat diet (HFD)–induced MASLD mouse model, which exhibited hallmark features of metabolic dysfunction, including significant body fat accumulation and elevated serum levels of pro-inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α[TNF-α]). Behavioral assays demonstrated pronounced anxiety-like 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-driven disruption of hippocampal circuits. At the molecular level, MASLD altered the expression of key hippocampal genes—including TCF7L2, LCN2, and AQP1—impacting 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-level evidence for MASLD–related 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–brain axis. This study highlights key genes and pathways underlying MASLD–induced cognitive impairment, advances understanding of metabolic-neural cross talk, and offers potential therapeutic targets for mitigating cognitive decline through intervention in the liver–brain axis, developing intervention strategies and highlight the therapeutic promise of targeting the liver–brain axis.