Acute liver failure (ALF) is a condition with high mortality and morbidity, characterized by GSH depletion, oxidative stress, and mitochondrial dysfunction. Ferroptosis may be involved in ALF. Indeed, emerging studies have demonstrated that ferroptosis plays a significant role in ALF. However, the mechanism of ferroptosis in hepatocytes during ALF remains unknown.Hepatic specific TGFβr1 knockout (TGFβr1Δhep-CKO) mice and nuclear factor erythroid 2-related factor 2 knockout（Nrf2-/-）mice were generated and subjected to ALF. Electron microscopy was used to detect mitochondrial and other cell substructure changes during ALF.In this study, we noticed that LPS/GalN induced caspases-mediated apoptosis as current research reported, we also found lipid peroxidation, ROS accumulation, and glutathione (GSH), coenzyme Q10 (CoQ10) system inhibition mediated ferroptosis during LPS/GalN induced-ALF. Rescue studies showed that ferrostatin-1(Fer-1) and Deferoxamine mesylate (DFMO), the inhibitor of ferroptosis, could alleviate LPS/GalN-induced ALF. Additionally, we noticed that TGFβ1 was increased during ALF, while ALF was relieved in TGFβr1Δhep-CKO mice. We also noticed that liver TGFβr1 deficiency alleviated LPS/GalN-induced apoptosis and ferroptosis by affecting the phosphorylation of glycogen synthase kinase3β (P-GSK3β) and nuclear factor erythroid 2-related factor 2(Nrf2), a key antioxidant factor, by up-regulating the levels of GPX4, XCT, DHODH and FSP1, and down-regulating TFR, Ptgs2, CHAC1, and POR expression. The further supplemental experiment showed that ferroptosis was significantly aggravated in Nrf2-/-mice compared with its WT controls and reversed by Fer-1.This study demonstrates that TGFβr1 plays a critical role in mediating LPS/GalN-induced ALF by promoting apoptosis and ferroptosis.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.