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