Center of TCM Preventive Treatment, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Traditional Chinese Medicine, People's Hospital of Yangjiang, Yangjiang 529500, China.
Int Immunopharmacol. 2024 Feb 15;128:111529. doi: 10.1016/j.intimp.2024.111529. Epub 2024 Jan 20.
Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) plays a crucial role in DNA base excision repair, cell apoptosis, cell signaling, and the regulation of transcription factors through redox modulation and the control of reactive oxygen species (ROS). However, the connection between APE1 and acute liver injury (ALI) remains enigmatic. This study aims to unravel the molecular mechanisms underlying ALI and shed light on the role of APE1 in this context.
We induced acute liver injury (ALI) in mice by lipopolysaccharide/D-galactosamine (LPS/GalN) and intervened with the APE1 inhibitor E3330. We examined the expression of APE1 in ALI mice and ALI patient tissues after E3330 intervention, Additionally, we measured hepatic oxidative stress, ferroptosis, and autophagy marker proteins and genes. In establishing an AML-12 liver cell injury model, we utilized the Nrf2 activator tert-butylhydroquinone (TBHQ) as an intervention and examined APE1, Nrf2, ferroptosis-related proteins, and autophagy marker proteins and mRNA.
Both ALI patients and ALI mice exhibited reduced APE1 expression levels. After E3330 intervention, there was a significant exacerbation of liver injury, oxidative stress, and a reduction in the expression of proteins, including GPX4, X-CT, ATG3, ATG5, and LC3 (LC3I/II). Consistent results were also observed in AML-12 cells. With TBHQ intervention, Nrf2 expression increased, along with the expression of proteins associated with iron death and autophagy. Mechanistically, APE1 activation regulates Nrf2 to inhibit ferroptosis and promote autophagy in hepatocytes.
The data suggest that APE1 is a pivotal player in ALI, closely linked to its regulation of Nrf2. Strategies involving APE1 activation to modulate Nrf2, thereby inhibiting hepatocyte ferroptosis and promoting autophagy, may represent innovative therapeutic approaches for ALI. Additionally, tert-butylhydroquinone (TBHQ) holds significant promise in the treatment of acute liver injury.
脱嘌呤/脱嘧啶核酸内切酶 1/氧化还原效应因子 1（APE1/Ref-1）在 DNA 碱基切除修复、细胞凋亡、细胞信号转导以及通过氧化还原调节和控制活性氧物种（ROS）来调控转录因子方面发挥着关键作用。然而，APE1 与急性肝损伤（ALI）之间的联系仍然是个谜。本研究旨在揭示 ALI 的分子机制，并阐明 APE1 在这方面的作用。
我们通过脂多糖/半乳糖胺（LPS/GalN）诱导小鼠急性肝损伤（ALI），并用 APE1 抑制剂 E3330 进行干预。我们检测了 ALI 小鼠和 E3330 干预后 ALI 患者组织中 APE1 的表达。此外，我们还测量了肝氧化应激、铁死亡和自噬标志物蛋白和基因。在建立 AML-12 肝细胞损伤模型时，我们利用 Nrf2 激活剂叔丁基对苯二酚（TBHQ）作为干预措施，检测了 APE1、Nrf2、铁死亡相关蛋白和自噬标志物蛋白和 mRNA。
ALI 患者和 ALI 小鼠均表现出 APE1 表达水平降低。E3330 干预后，肝损伤、氧化应激显著加重，GPX4、X-CT、ATG3、ATG5 和 LC3（LC3I/II）等蛋白表达降低。AML-12 细胞也观察到了一致的结果。TBHQ 干预后，Nrf2 表达增加，与铁死亡和自噬相关的蛋白表达增加。机制上，APE1 的激活调节 Nrf2 抑制肝细胞铁死亡并促进自噬。
数据表明，APE1 是 ALI 的关键调节因子，与它对 Nrf2 的调节密切相关。激活 APE1 以调节 Nrf2，从而抑制肝细胞铁死亡并促进自噬，可能为 ALI 提供新的治疗策略。此外，叔丁基对苯二酚（TBHQ）在急性肝损伤的治疗中有很大的潜力。
