Li Qianqian, Zhang Qianqian, Ren Aigang, Zhang Haiyan, Liu Lixin
Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical University, 85 South Jiefang Road, Taiyuan, 030012, Shanxi Province, China; Key Laboratory of Prevention and Treatment of Liver Injury and Digestive System Neoplasms, Provincial Committee of the Medical and Health, 85 South Jiefang Road, Taiyuan, 030012, Shanxi Province, China; Department of Gastroenterology and Hepatology, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi Province, China.
Key Laboratory of Prevention and Treatment of Liver Injury and Digestive System Neoplasms, Provincial Committee of the Medical and Health, 85 South Jiefang Road, Taiyuan, 030012, Shanxi Province, China.
Biochem Biophys Res Commun. 2025 Sep 12;779:152406. doi: 10.1016/j.bbrc.2025.152406. Epub 2025 Jul 25.
Metabolic dysfunction-associated steatohepatitis (MASH) is currently the fastest-growing cause of liver-related deaths. Intervention in the early stage of MASH will effectively reverse the condition and avoid huge health and economic burdens. To date, our understanding of MASH remains quite limited. Its pathogenesis remains not fully understood, and effective diagnostic and therapeutic tools are lacking. Although ferroptosis is closely related to MASH and seen as a promising target, its exact mechanism in the early stage of MASH remains unclear. This study aims to analyze the ferroptosis-related genes that are differentially expressed in early MASH, identify potential diagnostic markers, and provide a new perspective for further in-depth research on the role of ferroptosis in early MASH. Gene expression datasets of human MASH patients were obtained from the GEO database. The early MASH gene expression data from GSE126848 and GSE162694 were analyzed. Genes with significant P-values were subjected to GO enrichment analysis. After intersecting the obtained genes with those in the Ferroptosis Database (FerrDb), ferroptosis signature genes in early MASH were screened and then analyzed via PPI network. Four hub genes (FXN, FABP4, QSOX1, CAPG) were selected and validated in the GSE135251 dataset. Their diagnostic efficiency was evaluated using ROC curve analysis. In vitro and in vivo MASH models, including HFCFD-induced mouse models and FFA-induced mouse liver cells, confirmed their expression changes related to ferroptosis. Also, in human fibrotic liver tissues, three of these hub genes were highly expressed in macrophages. These four genes may serve as potential diagnostic biomarkers for early MASH.
代谢功能障碍相关脂肪性肝炎（MASH）是目前肝脏相关死亡人数增长最快的原因。在MASH早期进行干预将有效逆转病情，避免巨大的健康和经济负担。迄今为止，我们对MASH的了解仍然相当有限。其发病机制仍未完全阐明，且缺乏有效的诊断和治疗工具。尽管铁死亡与MASH密切相关并被视为一个有前景的靶点，但其在MASH早期的确切机制仍不清楚。本研究旨在分析早期MASH中差异表达的铁死亡相关基因，鉴定潜在的诊断标志物，并为进一步深入研究铁死亡在早期MASH中的作用提供新的视角。从GEO数据库获取人类MASH患者的基因表达数据集。分析来自GSE126848和GSE162694的早期MASH基因表达数据。对具有显著P值的基因进行GO富集分析。将获得的基因与铁死亡数据库（FerrDb）中的基因进行交叉，筛选出早期MASH中的铁死亡特征基因，然后通过蛋白质-蛋白质相互作用（PPI）网络进行分析。选择四个枢纽基因（FXN、FABP4、QSOX1、CAPG）并在GSE135251数据集中进行验证。使用ROC曲线分析评估它们的诊断效率。体外和体内MASH模型，包括高脂高糖饮食（HFCFD）诱导的小鼠模型和游离脂肪酸（FFA）诱导的小鼠肝细胞，证实了它们与铁死亡相关的表达变化。此外，在人类肝纤维化组织中，其中三个枢纽基因在巨噬细胞中高表达。这四个基因可能作为早期MASH的潜在诊断生物标志物。
