Li Chenjie, Yang Dongjie, Liu Ling, Zhao Shuiping, Zhao Wang
Department of Gastroenterology, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, China.
Department of Gastroenterology, the Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei 063003, China.
Biochem Pharmacol. 2025 Jul 4;240:117100. doi: 10.1016/j.bcp.2025.117100.
Inflammation and ferroptosis play important roles in metabolicdysfunction-associatedsteatoticliverdisease (MASLD) pathogenesis. It is necessary to identify inflammation-associated ferroptosis regulators (IAFRs) in MASLD progression and potential drugs for MASLD treatment. The MASLD-related dataset GSE49541 was analyzed to identify differentially expressed genes. Identification of crucial genes in MASLD pathogenesis was archived with WGCNA algorithm. Genes related to inflammation and ferroptosis were obtained from GSEA database and FerrDb database. After IAFRs were obtained from the intersection, virtual screening of natural drugs targeting early growth response protein 1 (EGR1) was performed. MASLD models were constructed, and treated with (-)Epicatechin (EPI) or not. Then the severity of MASLD in mice was evaluated by histological analysis, blood biochemical examination, etc., and the injury of in vitro hepatocytes was detected by cell viability assay, flow cytometry, etc. ELISA was applied to evaluate the inflammatory response, and reactive oxide species, iron load, and ferroptosis markers were detected. Western blot was used to detect the regulatory effects of EPI on NF-κB and Nrf2 pathways. Six IAFRs in MASLD pathogenesis were identified, including EGR1, GSTZ1, SLC38A1, FH, HELLS and MT1G. EPI had good binding affinity with EGR1, which reversed HFD-induced weight and liver weight gain in mice, and inhibit inflammatory response and ferroptosis, and effectively ameliorated liver injury. EPI also reduced free fatty acids-induced injury of hepatocytes. Additionally, EPI regulates lipid metabolism, inflammation, oxidative stress, and ferroptosis in MASLD mainly through NF-κB and Nrf2 pathways. Collectively, EPI targets EGR1 to ameliorate liver injury in MASLD.
炎症和铁死亡在代谢功能障碍相关脂肪性肝病（MASLD）的发病机制中起重要作用。有必要在MASLD进展过程中鉴定炎症相关铁死亡调节因子（IAFRs）以及用于MASLD治疗的潜在药物。分析了与MASLD相关的数据集GSE49541以鉴定差异表达基因。使用WGCNA算法确定了MASLD发病机制中的关键基因。从GSEA数据库和FerrDb数据库中获取与炎症和铁死亡相关的基因。从交集获得IAFRs后，对靶向早期生长反应蛋白1（EGR1）的天然药物进行虚拟筛选。构建MASLD模型，并给予（-）表儿茶素（EPI）或不给予。然后通过组织学分析、血液生化检查等评估小鼠MASLD的严重程度，并通过细胞活力测定、流式细胞术等检测体外肝细胞的损伤。应用ELISA评估炎症反应，并检测活性氧、铁负荷和铁死亡标志物。使用蛋白质免疫印迹法检测EPI对NF-κB和Nrf2通路的调节作用。鉴定出MASLD发病机制中的6种IAFRs，包括EGR1、GSTZ1、SLC38A1、FH、HELLS和MT1G。EPI与EGR1具有良好的结合亲和力，可逆转高脂饮食诱导的小鼠体重和肝脏重量增加，抑制炎症反应和铁死亡，并有效改善肝损伤。EPI还减少了游离脂肪酸诱导的肝细胞损伤。此外，EPI主要通过NF-κB和Nrf2通路调节MASLD中的脂质代谢、炎症、氧化应激和铁死亡。总体而言，EPI靶向EGR1以改善MASLD中的肝损伤。
