Yu Xingui, Zhou Jiawei, Wang Sitong, Lu Yang, Gu Yunyun, Wang Xiaohong
Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China.
Key Laboratory of Jiangsu Province University for Nucleic Acid & Cell Fate Manipulation, Yangzhou University, Yangzhou, 225001, China.
Mol Neurobiol. 2025 Aug 26. doi: 10.1007/s12035-025-05266-w.
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.
阿尔茨海默病（AD）和肝细胞癌（HCC）是常见的与年龄相关的疾病。虽然肠-肝-脑轴已得到认可，但AD和HCC中肝功能障碍与神经退行性变之间的分子联系仍不清楚。本研究调查了AD和HCC中共同失调的基因和通路，重点关注肝-脑轴和潜在的治疗靶点。我们采用了计算机模拟和体内实验相结合的方法。使用差异表达基因（DEG）分析和加权基因共表达网络分析（WGCNA）对AD和HCC的基因表达数据集（GEO）进行分析，以识别共表达模块和DEG。使用综合毒物数据库（CTD）和基因卡片（GeneCards）识别与疾病相关的共享基因。富集分析（京都基因与基因组百科全书KEGG、基因本体论GO）阐明其功能。蛋白质-蛋白质相互作用（PPI）网络和微小RNA靶标数据库（miRTarBase）确定了枢纽基因和调控性微小RNA。孟德尔随机化评估了共享的遗传风险因素。实时定量聚合酶链反应（qRT-PCR）和免疫组织化学验证了AD和HCC小鼠模型的脑（海马体、前额叶皮质）和肝组织中的研究结果。白细胞介素-6（IL-6）、基质金属蛋白酶9（MMP9）、转化生长因子β1（TGFB1）、热休克蛋白90α家族成员1（HSP90AA1）和信号转导和转录激活因子3（STAT3）被确定为AD和HCC中的关键共享基因，表明它们与神经炎症和肿瘤进展有关。富集分析突出了包括转化生长因子-β（TGF-β）和磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）在内的共享炎症通路。has-mir-29b-3p可能在这两种疾病中都发挥作用。孟德尔随机化确定CD28-CD25 ++ CD8 + T细胞为共享的遗传风险因素。在AD小鼠脑和HCC小鼠肝脏中证实了IL-6、MMP9和STAT3的表达增加。本研究揭示了AD和HCC中以关键枢纽基因为中心的共享炎症机制，可能受迷走神经调节。这些发现为进一步研究治疗靶点提供了依据。
