Mammalian cells have developed a variety of ways to induce cell death, which are important for diverse biological processes as well as disease control. Regulated forms of cell death include apoptosis and necroptosis among many others, which all are defined by the Nomenclature Committee on Cell Death (NCCD). In 2012, a novel type of cell death, ferroptosis, was characterized that results from lethal lipid peroxidation in an iron-dependent manner.(1) Although some individual aspects of this cell death pathway have been studied over the past decades, only in 2012 was the name ferroptosis coined by the Stockwell lab.(1) Thus, this study provided an important conceptual foundation that paved the way for a new field of cell death research. To date, limited information has been collected with regard to the physiological relevance of ferroptosis. The Zou lab demonstrated that immune clearance of tumor cells by CD8 T-cells during cancer immunotherapy employs ferroptosis, hence providing the first evidence that ferroptosis takes place under physiological conditions. With regard to disease association, ferroptosis is suggested as a driver of neurodegenerative diseases (e.g., Huntington’s and Alzheimer’s disease), stroke, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration,(2) thereby making ferroptosis inhibitors potential novel drug candidates for these diseases. In contrast, induction of ferroptosis has been described as a potent strategy for attacking responsive cancer entities. Cells have evolutionarily developed ways to block ferroptotic cell death. The central regulator that counteracts ferroptosis is the protein GPX4, which together with glutathione has antioxidant capacity to prevent lipid peroxidation and hence ferroptosis. Intriguingly, previous studies have demonstrated that pathways that are linked to ferroptosis inhibition all converge into GPX4/glutathione. These pathways include cystine import via the system x_c^–, cysteine production by the transsulfuration pathway, and selenocysteine production by the mevalonate pathway, all necessary for GPX4/glutathione synthesis/activation. In line with this, small molecules that directly inhibit GPX4 (e.g., RSL3) or indirectly inhibit GPX4 by targeting system x_c^– (e.g., Erastin) induce lipid peroxidation and ferroptotic cell death.(2) Interestingly, the mevalonate pathway also triggers synthesis of ubiquinone/coenzyme Q₁₀ (CoQ₁₀), which was suggested to inhibit ferroptosis in a report in 2016 by the Stockwell lab; however, findings about the exact contribution of ubiquinone in ferroptosis suppression were not fully conclusive by then. Two important back-to-back studies by Doll et al. and Bersuker et al. aimed to identify novel suppressors of ferroptosis that would act independently of the master regulator GPX4.(3,4) By using an overexpression screen in one study and a synthetic lethal CRISPR-Cas9 knockout screen in the other, both groups revealed the gene apoptosis-inducing factor mitochondrial 2 (AIFM2), which they renamed ferroptosis suppressor protein 1 (FSP1), to be protective against ferroptotic cell death. Importantly, FSP1 fully combats lethal peroxidation and ferroptosis in the absence of GPX4. Myristoylated FSP1 is tethered to the plasma membrane and acts as the critical enzyme to reduce ubiquinone to ubiquinol, thereby restoring the reduced pool. This reduced form of CoQ₁₀ is a potent antioxidant that counteracts lethal lipid peroxidation (Figure 1) through radical trapping.(3,4) Both studies further elaborated on the potential of FSP1 as a valid drug target for cancer therapy. Here, they found that levels of FSP1 correlate to the degree of ferroptosis resistance in many cancer cell lines. This implies that FSP1 can serve as a valuable target for responsive tumors to be treated with FSP1 inhibitors. This hypothesis was validated by Bersuker et al. in mouse tumor xenografts, and more excitingly, Doll et al. developed the first potent FSP1 inhibitors that triggered ferroptosis in various tumor cells. Future research by these two groups and others will provide insight into the exciting potential of FSP1 inhibitors to kill distinct tumors in preclinical and clinical settings. Figure 1. Suppression of ferroptotic cell death by FSP1. FSP1 and GPX4 act independently of each other to inhibit lipid peroxidation and ferroptosis. Interestingly, a recent publication by Kraft et al. reported on another highly potent endogenous ferroptosis suppressor, GTP cyclohydrolase 1 (GCH1), which is the rate-limiting enzyme for synthesis of the antioxidant tetrahydrobiopterin (BH₄). Like FSP1 and CoQ₁₀, GCH1 and BH₄ act entirely independently of GPX4 to block ferroptosis.(5) Also here, elevated levels of GCH1 could be linked to ferroptosis resistance, and therefore, this study marked GCH1 as a potential novel target for cancer therapy. This report further outlined that there may be even more GPX4-independent suppressors of ferroptotic cell death as they provide a host of genes that can inhibit lethal lipid peroxidation in the absence of GPX4. Together, the recent reports by Doll et al., Bersuker et al., and Kraft et al. markedly changed the landscape of ferroptosis research. Prior to these studies, there has been a strong and consistent dogma that GPX4 is the only gatekeeper to suppress ferroptosis. Now, the field has gained at least two more endogenous inhibitors, FSP1 and GCH1, which act in parallel with GPX4 as guardians to protect from ferroptosis. Future research will be important to draw a full picture on the number of master regulators that collaborate to control ferroptosis. Furthermore, smart strategies will be needed to inactivate these novel suppressors with selective drugs to provide innovative approaches for personalized cancer therapy. This work was supported by HelmholtzZentrum Muenchen GmbH core funding to K.H. The author declares no competing financial interest. This article references 5 other publications.

中文翻译：

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Ferroptosis抑制蛋白1（FSP1）和辅酶Q10协同抑制Ferroptosis。

哺乳动物细胞已经开发出多种诱导细胞死亡的方法，这对于多种生物过程以及疾病控制都很重要。细胞死亡的受规管形式包括细胞凋亡和坏死性坏死病，这些均由细胞死亡命名委员会（NCCD）定义。2012年，一种新型的细胞死亡，即肥大症，其特征是致命的脂质过氧化作用以铁依赖性方式引起。（1）尽管过去几十年来已经研究了这种细胞死亡途径的某些个别方面，但仅在2012年（1）因此，本研究提供了重要的概念基础，为细胞死亡研究的新领域铺平了道路。迄今为止，关于受铁症病的生理相关性的信息很少。Zou实验室证明，在癌症免疫疗法中CD8 T细胞对肿瘤细胞的免疫清除作用是利用肥大症，因此提供了肥大症是在生理条件下发生的第一个证据。关于疾病的关联，建议将铁锈病作为神经退行性疾病（例如，亨廷顿氏病和阿尔茨海默氏病），中风，脑外伤，局部缺血-再灌注损伤和肾脏变性的驱动因素，（2）从而使铁锈病抑制剂成为潜在的新型药物候选物。对于这些疾病。相反，已经描述了诱导肥大病是攻击反应性癌症实体的有效策略。细胞在进化上已经发展出了阻止肥大细胞死亡的方法。对抗铁锈病的中央调节剂是蛋白质GPX4，谷胱甘肽与谷胱甘肽一起具有抗氧化能力，可防止脂质过氧化，进而预防肥大症。有趣的是，以前的研究表明，与抑制铁锈病有关的途径都汇聚到GPX4 /谷胱甘肽中。这些途径包括通过系统导入胱氨酸x_c ^–，通过转硫途径生产半胱氨酸和通过甲羟戊酸途径生产硒代半胱氨酸，这些都是GPX4 /谷胱甘肽合成/激活所必需的。与此相符，通过靶向系统x _c ^–直接抑制GPX4（例如RSL3）或间接抑制GPX4的小分子诱导脂质过氧化和肥大细胞的死亡。（2）有趣的是，甲羟戊酸途径还触发了合成醌/辅酶Q ₁₀（CoQ ₁₀），Stockwell实验室在2016年的一份报告中建议抑制铁锈病；然而，那时关于泛醌在促红细胞增多症抑制中的确切作用的发现尚无定论。Doll等人进行了两项重要的背对背研究。和Bersuker等。（3,4）通过一项研究中的过表达筛选和另一项研究中的合成致死性CRISPR-Cas9敲除筛选，两组均揭示了基因凋亡-诱导因子线粒体2（AIFM2）将其重命名为肥大病抑制蛋白1（FSP1），以防止肥大细胞死亡。重要的是，在没有GPX4的情况下，FSP1可以完全抵抗致命的过氧化和铁锈病。肉豆蔻酰化的FSP1被束缚在质膜上，并作为将泛醌还原为泛醇的关键酶，从而恢复了还原池。CoQ的这种简化形式₁₀是一种有效的抗氧化剂，可通过自由基捕获作用来抵消致命的脂质过氧化作用（图1）。（3,4）两项研究均进一步阐述了FSP1作为癌症治疗有效药物靶点的潜力。在这里，他们发现FSP1的水平与许多癌细胞系中抗铁锈病的程度有关。这意味着FSP1可以作为要用FSP1抑制剂治疗的反应性肿瘤的重要靶标。Bersuker等人证实了这一假设。在小鼠肿瘤异种移植中，更令人兴奋的是，Doll等人。开发了第一种有效的FSP1抑制剂，可在各种肿瘤细胞中引发肥大症。这两个小组及其他小组的未来研究将提供洞察力，以了解FSP1抑制剂在临床前和临床环境中杀死不同肿瘤的令人兴奋的潜力。图1。FSP1抑制肥大细胞死亡。FSP1和GPX4彼此独立发挥作用，以抑制脂质过氧化和肥大症。有趣的是，卡夫等人的最新出版物。报道了另一种高效内源性肥大症抑制因子GTP环水解酶1（GCH1），它是合成抗氧化剂四氢生物蝶呤（BH）的限速酶₄）。像FSP1和CoQ _10一样，GCH1和BH ₄（5）此外，GCH1水平的升高可能与抗铁锈病有关，因此，这项研究将GCH1标记为潜在的新型癌症治疗靶标。该报告进一步概述了可能存在更多的不依赖GPX4的肥大细胞死亡抑制剂，因为它们提供了在不存在GPX4的情况下可以抑制致死脂质过氧化的基因。总之，Doll等人，Bersuker等人和Kraft等人的最新报道。显着改变了肥育研究领域。在进行这些研究之前，一直存在一种强烈而一致的教条，即GPX4是抑制铁锈病的唯一看门人。现在，该领域至少获得了另外两种内源性抑制剂FSP1和GCH1，它们与GPX4并行充当保护者免受铁锈病的侵害。未来的研究对于全面了解协作控制肥大病的主要监管者的数量将非常重要。此外，将需要明智的策略来用选择性药物灭活这些新型抑制剂，以提供个性化癌症治疗的创新方法。这项工作得到了HelmholtzZentrum Muenchen GmbH向KH提供的核心资助的支持。作者声明没有任何竞争性的财务利益。本文引用了其他5个出版物。作者声明没有竞争性的经济利益。本文引用了其他5个出版物。作者声明没有竞争性的经济利益。本文引用了其他5个出版物。