BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening condition with limited treatment options beyond liver transplantation in non-acetaminophen cases. The extensive loss of liver function results from severe hepatocyte death, where elevated reactive oxygen species (ROS) play a significant role. Nuclear factor erythroid-2 like 2 (Nrf2) is crucial in ROS defence by regulating genes like glutathione peroxidase 4 (GPX4), which prevents lipid peroxidation (LPO). GPX4 is involved in several regulated cell processes, including apoptosis and ferroptosis. METHODS: GPX4 expression was measured in liver samples from healthy, ALF, and acute-on-chronic liver failure (ACLF) patients. To investigate GPX4's role, mice with hepatocyte-specific deletion of Gpx4 (Gpx4(Δhepa)) and both Gpx4 and the Nrf2 repressor, Keap1, (Gpx4(Δhepa)Keap1(Δhepa)) were generated. ALF was induced in mice using carbon tetrachloride (CCl(4)) and bile duct ligation (BDL) cholestasis models, each lasting 48 h. RESULTS: ALF patients exhibited reduced GPX4 levels compared to healthy individuals and ACLF patients, consistent with observations in CCl(4)-treated wild-type mice. ALF-induced Gpx4(Δhepa) mice exhibited increased hepatocyte death and liver dysfunction upon CCl(4), with increased apoptosis despite no changes in LPO markers. Activation of Nrf2 in Gpx4(Δhepa)Keap1(Δhepa) mice reversed CCl(4)-induced damage, reducing necrosis and apoptosis markers while inducing anti-apoptotic BCL2. CONCLUSION: Our results demonstrate that Gpx4 plays a critical role in ALF as its absence exacerbates apoptosis. Activating Keap1-dependent pathways targeting antioxidant defence systems and upregulating BCL2 provides substantial protection against ALF in mice lacking Gpx4 in hepatocytes. Our findings suggest that the Keap1-Nrf2 axis is a promising therapeutic target in ALF.