德国发育遗传学研究所Marcus Conrad和维尔茨堡大学José Pedro Friedmann Angeli等研究人员合作发现，FSP1是一种谷胱甘肽非依赖性铁死亡抑制因子。相关论文2019年10月21日在线发表于《自然》杂志。
研究人员采取了一种表达克隆的方法来鉴定能够弥补谷胱甘肽过氧化物酶4（GPX4）缺失的基因。这些工作鉴定了黄素蛋白“凋亡诱导因子线粒体相关蛋白2（AIFM2）”是以前未知的抗铁死亡基因。AIFM2（此后更名为“ ferroptosis-suppressor-protein 1”，简称为FSP1，最初被描述为促凋亡基因），赋予了针对GPX4缺失引起的铁死亡前所未有的保护作用。
研究人员进一步证明，FSP1可以通过泛醌（CoQ10）抑制铁死亡：其还原形式泛醇捕获介导脂质过氧化作用的脂质过氧自由基，而FSP1通过使用NAD（P）H催化其再生。FSP1的药理靶向作用与GPX4抑制剂可产生强烈协同作用，从而引发许多癌症个体的铁死亡。总之，FSP1/CoQ10/NAD（P）H作为独立的并行系统存在，可与GPX4和谷胱甘肽（GSH）协同作用来抑制磷脂过氧化（pLPO）和铁死亡。
据悉，铁死亡是一种铁依赖性形式的坏死性细胞死亡，其特征在于磷脂的氧化损伤。迄今为止，铁死亡被认为仅通过磷脂氢过氧化物（PLOOH）还原酶谷胱甘肽过氧化物酶4（GPX4）和自由基捕获抗氧化剂（RTA）所抑制。但是，特定细胞类型对铁死亡的敏感性因素对于了解铁死亡的病理生理作用以及如何将其用于癌症治疗至关重要。尽管代谢限制因素和磷脂成分促进了铁死亡的敏感性，但尚未发现引起铁死亡抗性的细胞本身机制。
附：英文原文
Title:FSP1 is a glutathione-independent ferroptosis suppressor
Author:Sebastian Doll, Florencio Porto Freitas, Ron Shah, Maceler Aldrovandi, Milene Costa da Silva, Irina Ingold, Andrea Goya Grocin, Thamara Nishida Xavier da Silva, Elena Panzilius, Christina Scheel, André Mourão, Katalin Buday, Mami Sato, Jonas Wanninger, Thibaut Vignane, Vaishnavi Mohana, Markus Rehberg, Andrew Flatley, Aloys Schepers, Andreas Kurz, Daniel White, Markus Sauer, Michael Sattler, Edward William Tate, Werner Schmitz, Almut Schulze, Valerie O’Donnel, Bettina Proneth, Grzegorz M. Popowicz, Derek Pratt, José Pedro Friedmann Angeli & Marcus Conrad
Issue&Volume:21 October 2019
Abstract:
Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been believed to be restrained only by the phospholipid hydroperoxide (PLOOH)-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants (RTAs)5,6. The factors which underlie a given cell type’s sensitivity to ferroptosis7 are, however, critical to understand the pathophysiological role of ferroptosis and how it may be exploited for cancer treatment. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been yet been identified that account for ferroptosis resistance. We undertook an expression cloning approach to identify genes able to complement GPX4 loss. These efforts uncovered the flavoprotein “apoptosis inducing factor mitochondria-associated 2 (AIFM2)” as a previously unrecognized anti-ferroptotic gene. AIFM2, hereafter renamed “ferroptosis-suppressor-protein 1” (FSP1), initially described as a pro-apoptotic gene11, confers an unprecedented protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that ferroptosis suppression by FSP1 is mediated via ubiquinone (CoQ10): its reduced form ubiquinol traps lipid peroxyl radicals that mediate lipid peroxidation, while FSP1 catalyses its regeneration by using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, FSP1/CoQ10/NAD(P)H exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione (GSH) to suppress phospholipid peroxidation (pLPO) and ferroptosis.
DOI:10.1038/s41586-019-1707-0
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
