1. Academic Validation
  2. Inhibitor of nuclear factor kappa B kinase subunit epsilon regulates murine acetaminophen toxicity via RIPK1/JNK

Inhibitor of nuclear factor kappa B kinase subunit epsilon regulates murine acetaminophen toxicity via RIPK1/JNK

  • Cell Biol Toxicol. 2023 Feb 9. doi: 10.1007/s10565-023-09796-8.
Yujie Xu # 1 Haozhe Xu # 2 Tao Ling # 2 Yachao Cui 1 Junwei Zhang 1 Xianmin Mu 2 Desheng Zhou 1 Ting Zhao 1 Yingchang Li 1 Zhongping Su 3 Qiang You 4 5
Affiliations

Affiliations

  • 1 Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China.
  • 2 Department of Biotherapy, Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
  • 3 Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China. suzhping@163.com.
  • 4 Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China. qiang.you@live.com.
  • 5 Department of Biotherapy, Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China. qiang.you@live.com.
  • # Contributed equally.
Abstract

Drug-induced liver injury (DILI) still poses a major clinical challenge and is a leading cause of acute liver failure. Inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE) is essential for inflammation and metabolic disorders. However, it is unclear how IKBKE regulates cellular damage in acetaminophen (APAP)-induced acute liver injury. Here, we found that the deficiency of IKBKE markedly aggravated APAP-induced acute liver injury by targeting RIPK1. We showed that APAP-treated IKBKE-deficient mice exhibited severer liver injury, worse mitochondrial integrity, and enhanced glutathione depletion than wild-type mice. IKBKE deficiency may directly upregulate the expression of total RIPK1 and the cleaved RIPK1, resulting in sustained JNK activation and increased translocation of RIPK1/JNK to mitochondria. Moreover, deficiency of IKBKE enhanced the expression of pro-inflammatory factors and inflammatory cell infiltration in the liver, especially neutrophils and monocytes. Inhibition of RIPK1 activity by necrostatin-1 significantly reduced APAP-induced liver damage. Thus, we have revealed a negative regulatory function of IKBKE, which acts as an RIPK1/JNK regulator to mediate APAP-induced hepatotoxicity. Targeting IKBKE/RIPK1 may serve as a potential therapeutic strategy for acute or chronic liver injury.

Keywords

Acetaminophen; IKBKE; JNK; Liver injury; RIPK1.

Figures
Products