Mendelian Randomization in Conjunction with WGCNA Was Employed to Investigate the Potential Role of the Liver-Brain Axis in the Pathogenesis of Hepatocellular Carcinoma and Alzheimer's Disease.

Alzheimer's disease (AD) and hepatocellular carcinoma (HCC) are prevalent age-related diseases. While the gut-liver-brain axis is recognized, the molecular links between liver dysfunction and neurodegeneration in AD and HCC remain unclear. This study investigated shared dysregulated genes and pathways in AD and HCC, focusing on the liver-brain axis and potential therapeutic targets. We used combined in silico and in vivo approaches. Gene expression datasets (GEO) for AD and HCC were analyzed using DEG analysis and WGCNA to identify co-expressed modules and DEGs. Shared disease-associated genes were identified using CTD and GeneCards. Enrichment analysis (KEGG, GO) elucidated functions. PPI networks and miRTarBase identified hub genes and regulatory miRNAs. Mendelian randomization assessed shared genetic risk factors. qRT-PCR and immunohistochemistry validated findings in brain (hippocampus, prefrontal cortex) and liver tissues from AD and HCC mouse models. IL-6, MMP9, TGFB1, HSP90AA1, and STAT3 were identified as key shared genes in AD and HCC, implicating them in neuroinflammation and tumor progression. Enrichment analysis highlighted shared inflammatory pathways, including TGF-β and PI3K-Akt. has-mir-29b-3p potentially plays a role in both diseases. Mendelian randomization identified CD28-CD25 + + CD8 + T cells as a shared genetic risk factor. Increased expression of IL-6, MMP9, and STAT3 was confirmed in AD mouse brains and HCC mouse livers. This study reveals shared inflammatory mechanisms in AD and HCC, centered on key hub genes, potentially modulated by the vagus nerve. These findings inform further investigation of therapeutic targets.