Inositol-requiring enzyme 1 alpha endoribonuclease specific inhibitor STF-083010 protects the liver from thioacetamide-induced oxidative stress, inflammation and injury by triggering hepatocyte autophagy.

Abstract

Acute liver injury caused by toxins or drugs is a common condition that threatens patients' lives. Inositol-requiring enzyme 1 alpha (IRE1α), the most conserved endoplasmic reticulum (ER) stress sensor, has been implicated in the pathophysiology of liver injury. Activated IRE1α endoribonuclease (RNase) can splice X-box binding protein 1 (XBP1) mRNA to produce the sXBP1 transcription factor. STF-083010, a specific inhibitor of IRE1α RNase, has recently been suggested to exhibit anti-oxidant and anti-inflammatory properties in multiple injury models. However, it remains unknown whether STF-083010 has a protective effect against thioacetamide (TAA)-induced acute liver injury. Here, we demonstrated that IRE1α-sXBP1 signaling is involved in the development of TAA-induced acute liver injury and correlates with the severity of liver damage. STF-083010 protected against TAA-induced liver injury, as evidenced by higher survival rates in response to a lethal dose of TAA and less severe liver injury in response to a toxic dose of TAA. Mechanistic exploration showed that STF-083010 triggered hepatocyte autophagy in response to TAA stimulation both in vivo and in vitro, leading to reduced reactive oxygen species (ROS) production and attenuated hepatic inflammation. We also found that Beclin-1 played a critical role in STF-083010-mediated autophagy in response to TAA stimulation. Autophagy inhibition by chloroquine (CQ) in vivo and Beclin-1 knockdown in vitro markedly abrogated the protective role of STF-083010 against TAA-induced oxidative stress, inflammation and hepatotoxicity. Our results suggested STF-083010 as a potential therapeutic application to prevent TAA-induced acute liver injury.

• Authors: Feng Zhan, Guoping Zhao, Xu Li, Shikun Yang, Wenjie Yang, Shun Zhou, Feng Zhang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 73 Pg. 261-269 (Aug 2019) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 31121416 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Antioxidants
• Cytokines
• Reactive Oxygen Species
• STF 083010
• Sulfonamides
• Thiophenes
• Thioacetamide
• Ern1 protein, mouse
• Protein Serine-Threonine Kinases
• Endoribonucleases

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Antioxidants (pharmacology, therapeutic use)
• Autophagy (drug effects)
• Cells, Cultured
• Chemical and Drug Induced Liver Injury (drug therapy, genetics, pathology)
• Cytokines (genetics)
• Endoribonucleases (antagonists & inhibitors)
• Hepatocytes (drug effects, metabolism)
• Male
• Mice, Inbred C57BL
• Oxidative Stress (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Reactive Oxygen Species (metabolism)
• Sulfonamides (pharmacology, therapeutic use)
• Thioacetamide
• Thiophenes (pharmacology, therapeutic use)