德国慕尼黑亥姆霍兹中心Marcus Conrad课题组发现，FSP1的相分离促进铁死亡。相关论文于2023年6月28日在线发表于国际学术期刊《自然》。
研究人员表示，铁死亡正在演变为一种非常有前途的方法，以对抗难以治疗的肿瘤实体，包括治疗难治性和去分化的癌症。最近，铁死亡抑制蛋白-1（FSP1）与线粒体外泛醌或外源性维生素K和NAD（P）H/H+作为电子供体，已被确定为第二个铁死亡抑制系统，它可以有效地防止脂质过氧化，并独立于胱氨酸-谷胱甘肽（GSH）-谷胱甘肽过氧化物酶4（GPX4）轴。
为了开发FSP1抑制剂作为下一代治疗性铁死亡诱导剂，研究人员进行了小分子库筛选，并确定了3-苯基喹唑啉酮类化合物（以icFSP1为代表）作为有效的FSP1抑制剂。结果表明，icFSP1与iFSP1（第一个描述的靶向FSP1抑制剂）不同，不会竞争性地抑制FSP1酶的活性，而是引发FSP1从膜上的亚细胞重定位和FSP1凝聚，在铁死亡诱导前与GPX4抑制协同作用。icFSP1诱导的FSP1凝聚物显示出与相分离一致的液滴状特性，这是一种新兴和广泛的生物活性调节机制。FSP1的N端肉豆蔻化、不同的氨基酸残基和内在无序的低复杂度区域被确认为是FSP1在细胞和体外依赖性相分离的关键。
研究人员进一步证明，icFSP1会损害肿瘤的生长，并在体内的肿瘤中诱导FSP1凝聚。因此，这些结果表明，icFSP1表现出一种独特的作用机制，并与铁死亡诱导剂协同作用，增强铁死亡细胞的死亡反应，从而为靶向FSP1依赖性相分离作为一种有效的抗癌疗法提供了理论依据。
附：英文原文
Title: Phase separation of FSP1 promotes ferroptosis
Author: Nakamura, Toshitaka, Hipp, Clara, Santos Dias Mouro, Andr, Borggrfe, Jan, Aldrovandi, Maceler, Henkelmann, Bernhard, Wanninger, Jonas, Mishima, Eikan, Lytton, Elena, Emler, David, Proneth, Bettina, Sattler, Michael, Conrad, Marcus
Issue&Volume: 2023-06-28
Abstract: Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1,2,3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H+ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis4,5,6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity7. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.
DOI: 10.1038/s41586-023-06255-6
Source: https://www.nature.com/articles/s41586-023-06255-6
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
