丙型肝炎病毒 (HCV) 通过表观遗传学改变基因表达，以对其生命周期有利的方式重新排列细胞微环境。 HCV引起的宿主表观遗传变化导致代谢功能障碍和恶变。赖氨酸特异性去甲基酶 1 (LSD1) 是 HCV 传播所必需的关键细胞功能的表观遗传控制器。我们利用基因工程和药物抑制来改变内源性 LSD1 水平，研究了 LSD1 在 HCV 感染建立中的假定作用。我们首次证明，HCV 复制在 LSD1 过表达细胞中受到抑制，而特定的 HCV 蛋白则差异性地微调内源性 LSD1 表达水平。对全长 HCV 基因组和 LSD1 过表达中的亚基因组复制子进行电穿孔增强了翻译并部分恢复了 HCV 复制，表明 HCV 在感染的早期阶段可能受到 LSD1 的抑制。相反，抑制LSD1，然后在体外感染HCV，会增加病毒复制。 LSD1 被证明参与了一种有趣的抗病毒机制，它通过去甲基化激活内溶酶体干扰素诱导的跨膜蛋白 3 (IFITM3)，导致内吞的 HCV 病毒体降解。我们的研究提出，在整个慢性 HCV 感染过程中，HCV 介导的 LSD1 在无数病毒生命周期中的振荡可能会促进与 HCV 诱导的肝癌发生相关的表观遗传变化。

Hepatitis C virus (HCV) alters gene expression epigenetically to rearrange the cellular microenvironment in a beneficial way for its life cycle. The host epigenetic changes induced by HCV lead to metabolic dysfunction and malignant transformation. Lysine-specific demethylase 1 (LSD1) is an epigenetic controller of critical cellular functions that are essential for HCV propagation. We investigated the putative role of LSD1 in the establishment of HCV infection using genetic engineering and pharmacological inhibition to alter endogenous LSD1 levels. We demonstrated for the first time that HCV replication was inhibited in LSD1-overexpressing cells, while specific HCV proteins differentially fine-tuned endogenous LSD1 expression levels. Electroporation of the full-length HCV genome and subgenomic replicons in LSD1 overexpression enhanced translation and partially restored HCV replication, suggesting that HCV might be inhibited by LSD1 during the early steps of infection. Conversely, the inhibition of LSD1, followed by HCV infection in vitro, increased viral replication. LSD1 was shown to participate in an intriguing antiviral mechanism, where it activates endolysosomal interferon-induced transmembrane protein 3 (IFITM3) via demethylation, leading endocytosed HCV virions to degradation. Our study proposes that HCV-mediated LSD1 oscillations over countless viral life cycles throughout chronic HCV infection may promote epigenetic changes related to HCV-induced hepatocarcinogenesis.