铁死亡在非酒精性脂肪性肝病纤维化期的作用机制

The mechanism of ferroptosis in fibrosis stage of nonalcoholic fatty liver disease

铁死亡(ferroptosis)是一种铁依赖的程序性细胞死亡方式,参与多种疾病的发生发展,包括神经退行性疾病、心脑血管疾病、肿瘤和肝脏代谢性疾病等。在非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)中,铁死亡通过芬顿反应引发细胞死亡,从而诱导非酒精性脂肪肝(nonalcoholic fatty liver,NAFL)向非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)以及肝纤维化发展。目前由NAFLD导致的肝纤维化患病人数日益增加,引起了一系列不良后果。但研究发现,特异性诱导肝纤维化小鼠模型中肝星状细胞(hepatic stellate cells,HSCs)铁死亡能够抑制HSCs转分化为肌成纤维细胞,减少细胞外基质(extracellular matrix,ECM)沉积,发挥抗纤维化作用,提示铁死亡成为NAFLD纤维化阶段的新型治疗靶点。本文将重点探讨铁死亡在NAFLD纤维化发展中的双重作用以及肝纤维化模型中铁死亡相关分子靶点、药物缓解肝纤维化的机制,以期为NAFLD纤维化阶段的药物研发和临床治疗提供新的思路。

Ferroptosis is an iron-dependent programmed cell death that involved in the occurrence and development of a variety of diseases, including neurodegenerative diseases, cardiovascular and cerebrovascular diseases, tumors, and liver metabolic diseases. In nonalcoholic fatty liver disease(NAFLD), ferroptosis induces cell death through the Fenton reaction, thereby causing the progression of nonalcoholic fatty liver(NAFL) to nonalcoholic steatohepatitis(NASH) and liver fibrosis. The number of patients with liver fibrosis caused by NAFLD is increasing, resulting in a series of adverse consequences. However, recent studies have found that specifically inducing ferroptosis in hepatic stellate cells(HSCs) in mouse models of liver fibrosis can inhibit the transdifferentiation of HSCs into myofibroblasts and reduce the deposition of extracellular matrix(ECM), exhibiting anti-fibrosis effects, suggesting ferroptosis can be a new therapeutic target for NAFLD fibrosis stage. The review will focus on exploring the dual role of ferroptosis in the development of NAFLD fibrosis, as well as the mechanisms by which ferroptosis-related targets and drugs alleviate liver fibrosis in liver fibrosis models, providing new insights into drug development and clinical treatment in fibrosis stage of NAFLD.