PDF(Pubmed)
Abstract：
The nuclear factor erythroid 2 (NF-E2)-related factor 1 (NFE2L1, also known as Nrf1) is a highly conserved transcription factor that belongs to the CNC-bZIP subfamily. Its significance lies in its control over redox balance, proteasome activity, and organ integrity. Stress responses encompass a series of compensatory adaptations utilized by cells and organisms to cope with extracellular or intracellular stress initiated by stressful stimuli. Recently, extensive evidence has demonstrated that NFE2L1 plays a crucial role in cellular stress adaptation by 1) responding to oxidative stress through the induction of antioxidative responses, and 2) addressing proteotoxic stress or endoplasmic reticulum (ER) stress by regulating the ubiquitin-proteasome system (UPS), unfolded protein response (UPR), and ER-associated degradation (ERAD). It is worth noting that NFE2L1 serves as a core factor in proteotoxic stress adaptation, which has been extensively studied in cancer and neurodegeneration associated with enhanced proteasomal stress. In these contexts, utilization of NFE2L1 inhibitors to attenuate proteasome \"bounce-back\" response holds tremendous potential for enhancing the efficacy of proteasome inhibitors. Additionally, abnormal stress adaptations of NFE2L1 and disturbances in redox and protein homeostasis contribute to the pathophysiological complications of cardiovascular diseases, inflammatory diseases, and autoimmune diseases. Therefore, a comprehensive exploration of the molecular basis of NFE2L1 and NFE2L1-mediated diseases related to stress responses would not only facilitate the identification of novel diagnostic and prognostic indicators but also enable the identification of specific therapeutic targets for NFE2L1-related diseases.
摘要：
核因子红系2（NF-E2）相关因子1（NFE2L1，也称为Nrf1）是一种高度保守的转录因子，属于CNC-bZIP亚家族。它的意义在于它对氧化还原平衡的控制，蛋白酶体活性，和器官完整性。应激反应包括细胞和生物体用来应对由应激刺激引发的细胞外或细胞内应激的一系列补偿性适应。最近,大量证据表明，NFE2L1在细胞应激适应中起关键作用，1）通过诱导抗氧化反应来响应氧化应激，和2）通过调节泛素-蛋白酶体系统（UPS）解决蛋白毒性应激或内质网（ER）应激，未折叠蛋白反应（UPR），和ER相关降解（ERAD）。值得注意的是，NFE2L1是蛋白毒性应激适应的核心因子，已在与蛋白酶体应激增强相关的癌症和神经变性中进行了广泛研究。在这些背景下,利用NFE2L1抑制剂减轻蛋白酶体“反弹”反应对于增强蛋白酶体抑制剂的功效具有巨大潜力。此外,NFE2L1的异常应激适应和氧化还原和蛋白质稳态的紊乱有助于心血管疾病的病理生理并发症,炎症性疾病，和自身免疫性疾病。因此,全面探索NFE2L1和NFE2L1介导的与应激反应相关疾病的分子基础,不仅有助于鉴定新的诊断和预后指标,而且能够鉴定NFE2L1相关疾病的特异性治疗靶点.
