胃癌是一种死亡率较高的恶性肿瘤。最近，新出现的证据表明铁死亡是一种由铁 (Fe) 依赖性脂质过氧化诱导的细胞死亡的调节形式。核因子E2相关因子2（NRF2）是细胞内氧化稳态的关键调节因子，在控制脂质过氧化方面发挥着关键作用，与铁死亡过程密切相关。然而，NRF2在胃癌中影响铁死亡的分子机制仍有待研究。在我们的研究中，发现 NRF 2 可转录激活胃癌中醛酮还原酶 1 成员 B1 (AKR1B1) 的表达。 AKR1B1通过去除谷胱甘肽的醛基参与脂质代谢的调节。我们发现AKR1B1在胃癌中高表达并且与患者的不良预后相关。体外实验发现AKR1B1具有促进胃癌细胞增殖和侵袭的能力。 AKR1B1 通过减少活性氧积累和脂质过氧化，以及减少细胞内亚铁离子和丙二醛表达并增加谷胱甘肽表达来抑制 RSL3 诱导的胃癌铁死亡。我们的研究表明，AKR1B1 通过调节 GPX4、PTGS2 和 ACSL4 来抵抗 RSL3 诱导的铁死亡，这在异种移植裸鼠模型中得到了进一步证明。我们的工作揭示了 AKR1B1 在抵抗 RSL3 诱导的胃癌铁死亡中的关键作用。版权所有 © 2024。由 Elsevier Inc. 出版。

Gastric cancer is a malignant tumor associated with a high mortality rate. Recently, emerging evidence has shown that ferroptosis, a regulated form of cell death induced by iron (Fe)-dependent lipid peroxidation. Nuclear factor E2 related factor 2 (NRF2) is a key regulator of intracellular oxidation homeostasis that plays a pivotal role in controlling lipid peroxidation, which is closely related to the process of ferroptosis. However, the molecular mechanism of NRF2 on ferroptosis remains to be investigated in gastric cancer. In our study, NRF 2 was found to transcriptionally activate Aldo-keto reductase 1 member B1 (AKR1B1) expression in gastric cancer. AKR1B1 is involved in the regulation of lipid metabolism by removing the aldehyde group of glutathione. We found that AKR1B1 is highly expressed in gastric cancer and is associated with a poor prognosis of the patients. In vitro experiments found that AKR1B1 has the ability to promote the proliferation and invasion of gastric cancer cells. AKR1B1 inhibited RSL3-induced ferroptosis in gastric cancer by reducing reactive oxygen species accumulation and lipid peroxidation, as well as decreasing intracellular ferrous ion and malondialdehyde expression and increasing glutathione expression. Our study demonstrated that AKR1B1 resisted RSL3-induced ferroptosis by regulating GPX4, PTGS2 and ACSL4, which was further demonstrated in a xenograft nude mouse model. Our work reveals a critical role for the AKR1B1 in the resistance to RSL3-induced ferroptosis in gastric cancer.Copyright © 2024. Published by Elsevier Inc.