Hepatic NF‐κB‐Inducing Kinase and Inhibitor of NF‐κB Kinase Subunit α Promote Liver Oxidative Stress, Ferroptosis, and Liver Injury

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.