Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Jiangsu, Nanjing, 210008, China.
Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Jiangsu, Nanjing, 210002, China.
Cell Death Dis. 2023 Jul 6;14(7):400. doi: 10.1038/s41419-023-05913-x.
Drug-induced liver injury (DILI) is the leading cause of acute liver failure (ALF). Continuous and prolonged hepatic cellular oxidative stress and liver inflammatory stimuli are key signatures of DILI. DEAD-box helicase 3, X-linked (DDX3X) is a central regulator in pro-survival stress granule (SG) assembly in response to stress signals. However, the role of DDX3X in DILI remains unknown. Herein, we characterized the hepatocyte-specific role of DDX3X in DILI. Human liver tissues of DILI patients and control subjects were used to evaluate DDX3X expression. APAP, CCl4 and TAA models of DILI were established and compared between hepatocyte-specific DDX3X knockout (DDX3X) and wild-type control (DDX3X) mice. Hepatic expression of DDX3X was significantly decreased in the pathogenesis of DILI compared with controls in human and mice. Compared to DDX3X mice, DDX3X mice developed significant liver injury in multiple DILI models. DDX3X deficiency aggravates APAP induced oxidative stress and hepatocyte death by affecting the pro-survival stress granule (SG) assembly. Moreover, DDX3X deficiency induces inflammatory responses and causes pronounced macrophage infiltration. The use of targeted DDX3X drug maybe promising for the treatment of DILI in human.
药物性肝损伤（DILI）是急性肝衰竭（ALF）的主要原因。持续和长期的肝细胞氧化应激和肝脏炎症刺激是 DILI 的关键特征。X 连锁 DEAD 框解旋酶 3（DDX3X）是应激信号下细胞存活应激颗粒（SG）组装的核心调节剂。然而，DDX3X 在 DILI 中的作用尚不清楚。本研究旨在表征 DDX3X 在 DILI 中的肝细胞特异性作用。使用 DILI 患者和对照者的人肝组织评估 DDX3X 的表达。建立了 APAP、CCl4 和 TAA 诱导的 DILI 模型，并比较了肝细胞特异性 DDX3X 敲除（DDX3X）和野生型对照（DDX3X）小鼠之间的差异。与对照组相比，在人类和小鼠的 DILI 发病机制中，DDX3X 的肝表达明显降低。与 DDX3X 小鼠相比，DDX3X 小鼠在多种 DILI 模型中发生明显的肝损伤。DDX3X 缺乏通过影响生存应激颗粒（SG）组装，加重 APAP 诱导的氧化应激和肝细胞死亡。此外，DDX3X 缺乏诱导炎症反应并导致明显的巨噬细胞浸润。靶向 DDX3X 的药物治疗可能对人类 DILI 的治疗有一定的应用前景。
