Krainz Tanja, Gaschler Michael M, Lim Chaemin, Sacher Joshua R, Stockwell Brent R, Wipf Peter
Department of Chemistry, University of Pittsburgh , 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
Department of Biological Sciences and Department of Chemistry, Columbia University , 550 West 120th Street, Northwest Corner Building, MC 4846, New York, New York 10027, United States.
ACS Cent Sci. 2016 Sep 28;2(9):653-659. doi: 10.1021/acscentsci.6b00199. Epub 2016 Sep 7.
Discovering compounds and mechanisms for inhibiting ferroptosis, a form of regulated, nonapoptotic cell death, has been of great interest in recent years. In this study, we demonstrate the ability of XJB-5-131, JP4-039, and other nitroxide-based lipid peroxidation mitigators to prevent ferroptotic cell death in HT-1080, BJeLR, and panc-1 cells. Several analogues of the reactive oxygen species (ROS) scavengers XJB-5-131 and JP4-039 were synthesized to probe structure-activity relationships and the influence of subcellular localization on the potency of these novel ferroptosis suppressors. Their biological activity correlated well over several orders of magnitude with their structure, relative lipophilicity, and respective enrichment in mitochondria, revealing a critical role of intramitochondrial lipid peroxidation in ferroptosis. These results also suggest that preventing mitochondrial lipid oxidation might offer a viable therapeutic opportunity in ischemia/reperfusion-induced tissue injury, acute kidney injury, and other pathologies that involve ferroptotic cell death pathways.
近年来，发现抑制铁死亡（一种受调控的非凋亡性细胞死亡形式）的化合物和机制备受关注。在本研究中，我们证明了XJB - 5 - 131、JP4 - 039以及其他基于氮氧化物的脂质过氧化减轻剂能够预防HT - 1080、BJeLR和panc - 1细胞中的铁死亡性细胞死亡。合成了活性氧（ROS）清除剂XJB - 5 - 131和JP4 - 039的几种类似物，以探究构效关系以及亚细胞定位对这些新型铁死亡抑制剂效力的影响。它们的生物活性在几个数量级上与其结构、相对亲脂性以及在线粒体中的各自富集情况密切相关，揭示了线粒体内脂质过氧化在铁死亡中的关键作用。这些结果还表明，预防线粒体脂质氧化可能为缺血/再灌注诱导的组织损伤、急性肾损伤以及其他涉及铁死亡性细胞死亡途径的病理状况提供可行的治疗机会。
