丙型肝炎病毒（HCV）是一种病原体，其特点不仅是持久感染导致肝硬化和肝细胞癌（HCC）的发展，还表现为脂质和铁代谢紊乱等代谢性疾病。在慢性丙型肝炎患者的肝脏中常见高铁负荷，肝脏铁超载是一种高度促纤维化和致癌因素，增加了HCC的风险。然而，HCV感染肝脏中高铁积累的潜在机制尚未完全阐明。在这里，我们观察到HCV感染和表达来自重组腺病毒的病毒蛋白时细胞和肝脏组织中的铁积累。我们确定了两种分子机制，这些机制导致了HCV感染引起的细胞中铁负荷的增加。一种是肝细胞特异性的cAMP响应元件结合蛋白（CREBH）的转录诱导，这是调节铁稳态的关键激素hepcidin的启动子。HCV感染活化了CREBH转录因子，不仅直接识别hepcidin启动子，还诱导骨形态发生蛋白6（BMP6）的表达，从而激活BMP-SMAD信号通路，增强hepcidin启动子的活性。另一种是铁离子输出的膜蛋白ferroportin 1（FPN1）的翻译后调节，在胞内环区的Cys284和Ala285之间，由HCV NS3-4A丝氨酸蛋白酶介导的部分裂解。我们提出，内质网应激引发的宿主转录激活和病毒蛋白酶对FPN1的裂解共同作用于损害铁离子流出，导致HCV感染细胞中的铁积累。版权：©2023 Ohta等。本文为开放获取文章，依照知识共享署名许可证，允许在任何媒体中自由使用、分发和复制，前提是保留原作者和出处的署名。

Hepatitis C virus (HCV) is a pathogen characterized not only by its persistent infection leading to the development of cirrhosis and hepatocellular carcinoma (HCC), but also by metabolic disorders such as lipid and iron dysregulation. Elevated iron load is commonly observed in the livers of patients with chronic hepatitis C, and hepatic iron overload is a highly profibrogenic and carcinogenic factor that increases the risk of HCC. However, the underlying mechanisms of elevated iron accumulation in HCV-infected livers remain to be fully elucidated. Here, we observed iron accumulation in cells and liver tissues under HCV infection and in mice expressing viral proteins from recombinant adenoviruses. We established two molecular mechanisms that contribute to increased iron load in cells caused by HCV infection. One is the transcriptional induction of hepcidin, the key hormone for modulating iron homeostasis. The transcription factor cAMP-responsive element-binding protein hepatocyte specific (CREBH), which was activated by HCV infection, not only directly recognizes the hepcidin promoter but also induces bone morphogenetic protein 6 (BMP6) expression, resulting in an activated BMP-SMAD pathway that enhances hepcidin promoter activity. The other is post-translational regulation of the iron-exporting membrane protein ferroportin 1 (FPN1), which is cleaved between residues Cys284 and Ala285 in the intracytoplasmic loop region of the central portion mediated by HCV NS3-4A serine protease. We propose that host transcriptional activation triggered by endoplasmic reticulum stress and FPN1 cleavage by viral protease work in concert to impair iron efflux, leading to iron accumulation in HCV-infected cells.Copyright: © 2023 Ohta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.