小柯机器人

美国哈佛大学Stuart L. Schreiber、邹贻龙和怀特海生物医学研究所Robert A. Weinberg研究团队合作在研究中取得进展。他们发现了醚脂质的可塑性促进对铁死亡的敏感性和逃逸。该研究于2020年9月16日在线发表于国际学术期刊《自然》杂志。

研究人员使用全基因组CRISPR–Cas9抑制剂筛选确定了氧化细胞器过氧化物酶体是调控人肾和卵巢癌细胞铁死亡敏感性的关键因素。使用脂质组分析，研究人员发现过氧化物酶体通过合成多不饱合醚磷脂（PUFA-ePLs）促进铁死亡，PUFA-ePLs作为脂质过氧化的底物进而诱导铁死亡的发生。最初对铁死亡敏感的癌细胞可以在小鼠体内转换为铁死亡抵抗细胞，这与PUFA-ePL的广泛下调有关。

进一步研究发现，PUFA-ePLs促铁死亡作用可以从肿瘤细胞扩展到其他细胞类型，包括神经元和心肌细胞。总的来说，该研究工作揭示了过氧化物酶体-醚-磷脂通路在促进铁死亡敏感性和逃逸过程中的作用，强调了PUFA-ePL是一种独特的功能性脂质类别，在细胞状态转换过程中受到动态调节，并提供了对涉及铁死亡疾病的多个治疗性干预节点。

据了解，铁死亡是一种铁依赖性而非凋亡的细胞死亡方式，它与多种退行性疾病有关，在某些癌症中具有一定的靶向敏感性。铁死亡敏感性的细胞存在于某些谱系产生的细胞中，也可以在细胞状态转换过程中出现。但是，对于如何动态调控铁死亡敏感性仍然知之甚少。

附：英文原文

Title: Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

Author: Yilong Zou, Whitney S. Henry, Emily L. Ricq, Emily T. Graham, Vaishnavi V. Phadnis, Pema Maretich, Sateja Paradkar, Natalie Boehnke, Amy A. Deik, Ferenc Reinhardt, John K. Eaton, Bryan Ferguson, Wenyu Wang, Joshua Fairman, Heather R. Keys, Vlado Dank, Clary B. Clish, Paul A. Clemons, Paula T. Hammond, Laurie A. Boyer, Robert A. Weinberg, Stuart L. Schreiber

Issue&Volume: 2020-09-16

Abstract: Ferroptosis—an iron-dependent, non-apoptotic cell death process—is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers1. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions2,3,4,5. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR–Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome–ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis.

DOI: 10.1038/s41586-020-2732-8

Source: https://www.nature.com/articles/s41586-020-2732-8

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/
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