Cheng Yongwei, Song Zihao, Liu Ye, Xu Xichao, Zhang Dali, Zou Yigui, Liu Liang, Zeng Yinzhen, Li Wenwen, Bai Daming, Dai Dongling
Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases, Endoscopy Center and Gastroenterology Department, Shenzhen Children's Hospital, Shenzhen, China.
GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, China.
Front Oncol. 2024 Nov 4;14:1442221. doi: 10.3389/fonc.2024.1442221. eCollection 2024.
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by liver inflammation and damage caused by a buildup of fat in the liver. Hepatitis C, caused by hepatitis C virus (HCV), is a disease that can lead to liver cirrhosis, liver cancer, and liver failure. MASH and hepatitis C are the common causes of liver cirrhosis and hepatocellular carcinoma. Several studies have shown that hepatic steatosis is also a common histological feature of liver in HCV infected patients. However, the common molecular basis for MASH and hepatitis C remains poorly understood.
Firstly, differentially expressed genes (DEGs) for MASH and hepatitis C were extracted from the GSE89632, GSE164760 and GSE14323 datasets. Subsequently, the common DEGs shared among these datasets were determined using the Venn diagram. Next, a protein-protein interaction (PPI) network was constructed based on the common DEGs and the hub genes were extracted. Then, gene ontology (GO) and pathway analysis of the common DEGs were performed. Furthermore, transcription factors (TFs) and miRNAs regulatory networks were constructed, and drug candidates were identified. After the MASH and hepatitis C cell model was treated with predicted drug, the expression levels of the signature genes were measured by qRT-PCR and ELISA.
866 common DEGs were identified in MASH and hepatitis C. The GO analysis showed that the most significantly enriched biological process of the DEGs was the positive regulation of cytokine production. 10 hub genes, including STAT1, CCL2, ITGAM, PTPRC, CXCL9, IL15, SELL, VCAM1, TLR4 and CCL5, were selected from the PPI network. By constructing the TF-gene and miRNA-gene network, most prominent TFs and miRNAs were screened out. Potential drugs screening shows that Budesonide and Dinoprostone may benefit patients, and cellular experiments showed that Budesonide effectively inhibited the expression of genes related to glycolipid metabolism, fibrosis, and inflammatory factors.
We extracted 10 hub genes between MASH and hepatitis C, and performed a series of analyses on the genes. Molecular docking and studies have revealed that Budesonide can effectively suppress the progression of MASH and hepatitis C. This study can provide novel insights into the potential drug targets and biomarkers for MASH and hepatitis C.
代谢功能障碍相关脂肪性肝炎（MASH）的特征是肝脏中脂肪堆积导致肝脏炎症和损伤。丙型肝炎病毒（HCV）引起的丙型肝炎是一种可导致肝硬化、肝癌和肝衰竭的疾病。MASH和丙型肝炎是肝硬化和肝细胞癌的常见病因。多项研究表明，肝脂肪变性也是HCV感染患者肝脏的常见组织学特征。然而，MASH和丙型肝炎的共同分子基础仍知之甚少。
首先，从GSE89632、GSE164760和GSE14323数据集中提取MASH和丙型肝炎的差异表达基因（DEG）。随后，使用维恩图确定这些数据集中共享的共同DEG。接下来，基于共同DEG构建蛋白质-蛋白质相互作用（PPI）网络，并提取枢纽基因。然后，对共同DEG进行基因本体（GO）和通路分析。此外，构建转录因子（TF）和miRNA调控网络，并鉴定候选药物。在用预测药物处理MASH和丙型肝炎细胞模型后，通过qRT-PCR和ELISA测量特征基因 的表达水平。
在MASH和丙型肝炎中鉴定出866个共同DEG。GO分析表明，DEG中最显著富集的生物学过程是细胞因子产生的正调控。从PPI网络中选择了10个枢纽基因，包括STAT1、CCL2、ITGAM、PTPRC、CXCL9、IL15、SELL、VCAM1、TLR4和CCL5。通过构建TF-基因和miRNA-基因网络，筛选出最突出的TF和miRNA。潜在药物筛选表明，布地奈德和地诺前列酮可能使患者受益，细胞实验表明布地奈德有效抑制了与糖脂代谢、纤维化和炎症因子相关基因的表达。
我们在MASH和丙型肝炎之间提取了10个枢纽基因，并对这些基因进行了一系列分析。分子对接和研究表明，布地奈德可以有效抑制MASH和丙型肝炎 的进展。本研究可为MASH和丙型肝炎的潜在药物靶点和生物标志物提供新的见解。
