Hepatic NF‐κB‐Inducing Kinase and Inhibitor of NF‐κB Kinase Subunit α Promote Liver Oxidative Stress, Ferroptosis, and Liver Injury
| العنوان: | Hepatic NF‐κB‐Inducing Kinase and Inhibitor of NF‐κB Kinase Subunit α Promote Liver Oxidative Stress, Ferroptosis, and Liver Injury |
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| المؤلفون: | Yi Xiong, Xiao Zhong, Yong Liu, Yatrik M. Shah, Hong Shen, Zhiguo Zhang, Xue-Gong Fan, Liangyou Rui |
| المصدر: | Hepatology Communications, Vol 5, Iss 10, Pp 1704-1720 (2021) Hepatology Communications |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Programmed cell death, RC799-869, Protein Serine-Threonine Kinases, medicine.disease_cause, Mice, chemistry.chemical_compound, Liver disease, medicine, Animals, Ferroptosis, Phosphorylation, Protein Kinase Inhibitors, Acetaminophen, Liver injury, Hepatology, Chemistry, digestive, oral, and skin physiology, NF-κB, Original Articles, Diseases of the digestive system. Gastroenterology, medicine.disease, Liver regeneration, Liver Regeneration, Oxidative Stress, medicine.anatomical_structure, Liver, Hepatocyte, Hepatocytes, Cancer research, Original Article, Lipid Peroxidation, Liver function, Chemical and Drug Induced Liver Injury, Reactive Oxygen Species, Oxidative stress |
| الوصف: | Drug‐induced hepatotoxicity limits development of new effective medications. Drugs and numerous endogenous/exogenous agents are metabolized/detoxified by hepatocytes, during which reactive oxygen species (ROS) are generated as a by‐product. ROS has broad adverse effects on liver function and integrity, including damaging hepatocyte proteins, lipids, and DNA and promoting liver inflammation and fibrosis. ROS in concert with iron overload drives ferroptosis. Hepatic nuclear factor kappa B (NF‐κB)‐inducing kinase (NIK) is aberrantly activated in a broad spectrum of liver disease. NIK phosphorylates and activates inhibitor of NF‐κB kinase subunit alpha (IKKα), and the hepatic NIK/IKKα cascade suppresses liver regeneration. However, the NIK/IKKα pathway has not been explored in drug‐induced liver injury. Here, we identify hepatic NIK as a previously unrecognized mediator for acetaminophen (APAP)‐induced acute liver failure. APAP treatment increased both NIK transcription and NIK protein stability in primary hepatocytes as well as in liver in mice. Hepatocyte‐specific overexpression of NIK augmented APAP‐induced liver oxidative stress in mice and increased hepatocyte death and mortality in a ROS‐dependent manner. Conversely, hepatocyte‐specific ablation of NIK or IKKα mitigated APAP‐elicited hepatotoxicity and mortality. NIK increased lipid peroxidation and cell death in APAP‐stimulated primary hepatocytes. Pretreatment with antioxidants or ferroptosis inhibitors blocked NIK/APAP‐induced hepatocyte death. Conclusion: We unravel a previously unrecognized NIK/IKKα/ROS/ferroptosis axis engaged in liver disease progression. Hepatic NIK is upregulated in response to hepatic toxicants. Ablation of hepatic NIK attenuates, whereas hepatocyte‐specific overexpression of NIK aggravates, APAP‐induced liver injury. NIK promotes hepatic oxidative stress and ferroptosis. |
| تدمد: | 2471-254X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::396ba55de0694c8872057595c8698943 https://doi.org/10.1002/hep4.1757 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....396ba55de0694c8872057595c8698943 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2471254X |
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