Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
The University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
Mol Cells. 2023 Mar 31;46(3):165-175. doi: 10.14348/molcells.2023.0005. Epub 2023 Mar 24.
The transcription factor Nrf2 was originally identified as a master regulator of redox homeostasis, as it governs the expression of a battery of genes involved in mitigating oxidative and electrophilic stress. However, the central role of Nrf2 in dictating multiple facets of the cellular stress response has defined the Nrf2 pathway as a general mediator of cell survival. Recent studies have indicated that Nrf2 regulates the expression of genes controlling ferroptosis, an ironand lipid peroxidation-dependent form of cell death. While Nrf2 was initially thought to have anti-ferroptotic function primarily through regulation of the antioxidant response, accumulating evidence has indicated that Nrf2 also exerts anti-ferroptotic effects via regulation of key aspects of iron and lipid metabolism. In this review, we will explore the emerging role of Nrf2 in mediating iron homeostasis and lipid peroxidation, where several Nrf2 target genes have been identified that encode critical proteins involved in these pathways. A better understanding of the mechanistic relationship between Nrf2 and ferroptosis, including how genetic and/or pharmacological manipulation of Nrf2 affect the ferroptotic response, should facilitate the development of new therapies that can be used to treat ferroptosis-associated diseases.
转录因子 Nrf2 最初被鉴定为氧化还原平衡的主要调节剂，因为它调节参与减轻氧化和亲电应激的一系列基因的表达。然而，Nrf2 在决定细胞应激反应的多个方面的核心作用将 Nrf2 途径定义为细胞存活的一般介质。最近的研究表明，Nrf2 调节控制铁死亡的基因的表达，铁死亡是一种依赖于铁和脂质过氧化的细胞死亡形式。虽然最初认为 Nrf2 主要通过调节抗氧化反应来发挥抗铁死亡作用，但越来越多的证据表明，Nrf2 还通过调节铁和脂质代谢的关键方面来发挥抗铁死亡作用。在这篇综述中，我们将探讨 Nrf2 在调节铁平衡和脂质过氧化中的新作用，其中已经鉴定出几个 Nrf2 靶基因，它们编码这些途径中涉及的关键蛋白。更好地理解 Nrf2 与铁死亡之间的机制关系，包括遗传和/或药理学操纵 Nrf2 如何影响铁死亡反应，应有助于开发可用于治疗铁死亡相关疾病的新疗法。
