Shah Ron, Shchepinov Mikhail S, Pratt Derek A
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5.
Retrotope Inc., Los Altos, California 94022, United States.
ACS Cent Sci. 2018 Mar 28;4(3):387-396. doi: 10.1021/acscentsci.7b00589. Epub 2018 Feb 7.
Lipoxygenases (LOXs) have been implicated as central players in ferroptosis, a recently characterized cell death modality associated with the accumulation of lipid hydroperoxides: the products of LOX catalysis. To provide insight on their role, human embryonic kidney cells were transfected to overexpress each of the human isoforms associated with disease, 5-LOX, p12-LOX, and 15-LOX-1, which yielded stable cell lines that were demonstrably sensitized to ferroptosis. Interestingly, the cells could be rescued by less than half of a diverse collection of known LOX inhibitors. Furthermore, the cytoprotective compounds were similarly potent in each of the cell lines even though some were clearly isoform-selective LOX inhibitors. The cytoprotective compounds were subsequently demonstrated to be effective radical-trapping antioxidants, which protect lipids from autoxidation, the autocatalytic radical chain reaction that produces lipid hydroperoxides. From these data (and others reported herein), a picture emerges wherein LOX activity contribute to the cellular pool of lipid hydroperoxides that initiate ferroptosis, but lipid autoxidation drives the cell death process.
脂氧合酶（LOXs）被认为是铁死亡的核心参与者，铁死亡是一种最近被描述的细胞死亡方式，与脂质氢过氧化物的积累有关：脂质氢过氧化物是LOX催化的产物。为了深入了解它们的作用，将人胚胎肾细胞转染以过表达与疾病相关的每种人类亚型，即5-LOX、p12-LOX和15-LOX-1，从而产生了对铁死亡明显敏感的稳定细胞系。有趣的是，用不到一半的已知LOX抑制剂就能挽救这些细胞。此外，尽管有些是明显的亚型选择性LOX抑制剂，但细胞保护化合物在每个细胞系中的效力相似。随后证明细胞保护化合物是有效的自由基捕获抗氧化剂，可保护脂质免受自氧化，即产生脂质氢过氧化物的自催化自由基链反应。从这些数据（以及本文报道的其他数据）中可以看出，LOX活性有助于引发铁死亡的脂质氢过氧化物的细胞池，但脂质自氧化驱动细胞死亡过程。
