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.
Keyphrases
- drug induced
- liver injury
- nuclear factor
- toll like receptor
- oxidative stress
- liver failure
- cell death
- signaling pathway
- induced apoptosis
- poor prognosis
- wild type
- adverse drug
- protein kinase
- single cell
- transcription factor
- hepatitis b virus
- stem cells
- diabetic rats
- inflammatory response
- intensive care unit
- emergency department
- immune response
- drug delivery
- tyrosine kinase
- endoplasmic reticulum stress
- peripheral blood
- cancer therapy
- mesenchymal stem cells
- replacement therapy
- extracorporeal membrane oxygenation
- mechanical ventilation
- electronic health record
- high fat diet induced
- high glucose