Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine–Induced Acute Liver Failure Through Inhibiting GSK3β–Nrf2–Mediated Hepatocyte Apoptosis and Ferroptosis

作者：Sha Huang, Sicong Huang, Yuhua Wang, Shuwen Xie, Yuqi Lai, Chan Mo, Ting Zeng, Shanshan Kuang, Guanghui Deng, Chuying Zhou, Yuyao Chen, Sicong Huang, Sicong Huang, Lei Gao, Zhiping Lv · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2022 · DOI：10.1016/j.jcmgh.2022.02.009 · 被引用次数：108 · 研究领域：Ferroptosis and cancer prognosis、Liver physiology and pathology、TGF-β signaling in diseases

Background & Aims Acute liver failure (ALF) is a condition with high mortality and morbidity, characterized by glutathione depletion, oxidative stress, and mitochondrial dysfunction. Ferroptosis may be involved in ALF. Indeed, emerging studies have shown that ferroptosis plays a significant role in ALF. However, the mechanism of ferroptosis in hepatocytes during ALF remains unknown. Methods Hepatic-specific transforming growth factor β receptor 1 knockout (TGFβr1 Δhep-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. Results In this study, we noticed that lipopolysaccharide (LPS)/D-galactosamine (D-GalN) induced caspases-mediated apoptosis as current research reported, we also found lipid peroxidation, reactive oxygen species accumulation, and glutathione, co-enzyme Q10 system inhibition mediated ferroptosis during LPS/D-GalN-induced ALF. Rescue studies have shown that ferrostatin-1 (Fer-1) and deferoxamine mesylate (DFOM), the inhibitor of ferroptosis, could alleviate LPS/D-GalN-induced ALF. In addition, we noticed that TGFβ1 was increased during ALF, while ALF was relieved in TGFβr1 Δhep-CKO mice. We also noticed that liver TGFβr1 deficiency alleviated LPS/D-GalN-induced apoptosis and ferroptosis by affecting the phosphorylation of glycogen synthase kinase 3β and Nrf2, a key antioxidant factor, by up-reg...