Apart from APAP, established mice models also utilizes carbon tetrachloride (CCl4) or thioacetamide (TAA) to interpret the key aspects of DILI. Excess NAPQI formation due to APAP overdose overwhelms the antioxidant glutathione (GSH) reserves of liver, causing accumulating of cytotoxic adducts and subsequent hepatotoxicity. APAP is metabolized by cytochrome P450 isoforms into N-acetylbenzoquinoneimine (NAPQI). Acetaminophen (APAP) is the most well-studies drug which overdose induces hepatotoxicity and ALF. Drug-induced liver injury (DILI) has become a leading cause of acute liver failure (ALF) and transplantation. The liver is a major organ for drug metabolism and elimination. The use of targeted DDX3X drug maybe promising for the treatment of DILI in human. Moreover, DDX3X deficiency induces inflammatory responses and causes pronounced macrophage infiltration. DDX3X deficiency aggravates APAP induced oxidative stress and hepatocyte death by affecting the pro-survival stress granule (SG) assembly.
Compared to DDX3X fl/fl mice, DDX3X Δhep mice developed significant liver injury in multiple DILI models.
Hepatic expression of DDX3X was significantly decreased in the pathogenesis of DILI compared with controls in human and mice. APAP, CCl4 and TAA models of DILI were established and compared between hepatocyte-specific DDX3X knockout (DDX3X Δhep) and wild-type control (DDX3X fl/fl) mice. Human liver tissues of DILI patients and control subjects were used to evaluate DDX3X expression. Herein, we characterized the hepatocyte-specific role of DDX3X in DILI. However, the role of DDX3X in DILI remains unknown. DEAD-box helicase 3, X-linked (DDX3X) is a central regulator in pro-survival stress granule (SG) assembly in response to stress signals. Continuous and prolonged hepatic cellular oxidative stress and liver inflammatory stimuli are key signatures of DILI. Drug-induced liver injury (DILI) is the leading cause of acute liver failure (ALF).
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