丙型肝炎病毒 (HCV) 感染是慢性肝病的主要原因，已知会诱发内质网 (ER) 应激，从而改变细胞稳态和代谢过程。虽然 ER 应激与 HCV 相关疾病有关，但其确切作用仍不清楚。这项研究确定成纤维细胞生长因子 21 (FGF21) 是 HCV 感染显着上调的关键宿主因子。机制分析表明，HCV 对 FGF21 启动子的激活主要是由转录因子 ATF4 介导的，ATF4 通过 ER 应激诱导的 eIF2α 磷酸化而上调。此外，CREBH 激活进一步增强 ATF4 表达，有助于增加 FGF21 水平。 TRIB3 受 ATF4 上调，充当 FGF21 表达的负调节因子。该研究还确定了 HCV 感染细胞中 SOCS2 和 TRIM31 的 FGF21 依赖性上调。 SOCS2 有助于抑制 1 型干扰素信号传导，帮助病毒持续存在，而 TRIM31 促进肿瘤抑制蛋白 TSC 的降解，激活 mTORC1 通路并可能促进肝细胞增殖。这些发现表明，HCV 感染细胞中 FGF21 的上调可能在免疫反应调节和细胞增殖中发挥作用，从而导致持续的病毒感染和疾病进展。版权所有 © 2024 Liu, Ito, Sakai, Liu, Ohta, Saito, Nakashima,佐藤、绀野和铃木。

Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases and is known to induce endoplasmic reticulum (ER) stress, which alters cellular homeostasis and metabolic processes. While ER stress is implicated in HCV-related diseases, its precise role remains unclear. This study identifies fibroblast growth factor 21 (FGF21) as a key host factor significantly upregulated by HCV infection. Mechanistic analyses reveal that the activation of the FGF21 promoter by HCV is primarily mediated by the transcription factor ATF4, which is upregulated through the phosphorylation of eIF2α induced by ER stress. Additionally, CREBH activation further enhances ATF4 expression, contributing to increased FGF21 levels. TRIB3, upregulated by ATF4, acts as a negative regulator of FGF21 expression. The study also identifies FGF21-dependent upregulation of SOCS2 and TRIM31 in HCV-infected cells. SOCS2 contributes to the suppression of type 1 interferon signaling, aiding viral persistence, while TRIM31 promotes the degradation of the tumor suppressor protein TSC, activating the mTORC1 pathway and potentially promoting liver cell proliferation. These findings suggest that FGF21 upregulation in HCV-infected cells may play a role in both immune response regulation and cell proliferation, contributing to sustained viral infection and disease progression.Copyright © 2024 Liu, Ito, Sakai, Liu, Ohta, Saito, Nakashima, Satoh, Konno and Suzuki.