Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou, China.
Department of Gastroenterology, Peking University First Hospital, Beijing, China.
Oxid Med Cell Longev. 2021 Dec 20;2021:6551069. doi: 10.1155/2021/6551069. eCollection 2021.
Autoimmune hepatitis (AIH) is an inflammatory autoimmune disease of the liver. Oxidative stress triggered by reactive oxygen radicals is a common pathophysiological basis for the pathogenesis of many liver diseases, and ferroptosis is associated with the toxic accumulation of reactive oxygen species. The signaling transduction pathways responsible for iron processing and lipid-peroxidation mechanisms are believed to drive ferroptosis. However, the specific mechanisms regulating ferroptosis remain unclear. The aims of this investigation were to identify the possible effector functions of ferroptosis, based on glutathione peroxidase 4 (GPX4) regulation in an S100-induced autoimmune hepatitis mouse model and hepatocyte injury models. The S100 liver antigen-induced AIH mouse model was used to detect ferroptotic biomarkers using western blotting. Upregulated levels of cyclooxygenase2 (COX2) and Acyl-Coenzyme A synthase long-chain family member 4 (ACSL4) were observed in the S100-induced AIH model group, while levels of GPX4 and ferritin heavy chain 1 (FTH1) were downregulated ( < 0.05). The expression profiles of COX2, ACSL4, GPX4, and FTH1 were restored following the administration of ferrostatin-1. In addition, Nrf2 and HO-1 levels in the S100-induced AIH model mice after treatment with ferrostatin-1 were downregulated compared to the nonferrostatin-1-treated S100-induced AIH model mice ( < 0.05). Moreover, COX2 and ACSL4 levels were significantly upregulated, with significant FTH1 downregulation, in the AIH model mice when liver-specific GPX4 was silenced using AAV8 constructs. These data indicate that inhibition of ferroptosis significantly ameliorated the influence of AIH on the Nuclear factor E2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway, and that ferroptosis may act as an initiator or intermediate mediator leading to AIH.
自身免疫性肝炎（AIH）是一种肝脏的炎症性自身免疫性疾病。活性氧自由基引发的氧化应激是许多肝脏疾病发病机制的共同病理生理基础，而铁死亡与活性氧物种的毒性积累有关。铁处理和脂质过氧化机制的信号转导途径被认为驱动铁死亡。然而，调节铁死亡的确切机制尚不清楚。本研究旨在基于 S100 诱导的自身免疫性肝炎小鼠模型和肝细胞损伤模型中谷胱甘肽过氧化物酶 4（GPX4）的调节，确定铁死亡的可能效应功能。使用蛋白质印迹法在 S100 诱导的 AIH 小鼠模型中检测铁死亡生物标志物。在 S100 诱导的 AIH 模型组中观察到环氧化酶 2（COX2）和酰基辅酶 A 合成酶长链家族成员 4（ACSL4）水平上调，而 GPX4 和铁蛋白重链 1（FTH1）水平下调（<0.05）。用 ferrostatin-1 处理后，COX2、ACSL4、GPX4 和 FTH1 的表达谱得到恢复。此外，与未用 ferrostatin-1 处理的 S100 诱导的 AIH 模型小鼠相比，用 ferrostatin-1 处理后 S100 诱导的 AIH 模型小鼠中的核因子 E2 相关因子 2（Nrf2）/血红素加氧酶 1（HO-1）信号通路中的 Nrf2 和 HO-1 水平降低（<0.05）。此外，当使用 AAV8 构建物沉默肝特异性 GPX4 时，AIH 模型小鼠中的 COX2 和 ACSL4 水平显著上调，而 FTH1 水平显著下调。这些数据表明，抑制铁死亡显著改善了 AIH 对核因子 E2 相关因子 2（Nrf2）/血红素加氧酶 1（HO-1）信号通路的影响，并且铁死亡可能作为导致 AIH 的启动子或中间介质。
