The LIFR-targeting small molecules EC330/EC359 are potent ferroptosis inducers.
The LIFR-targeting small molecules EC330/EC359 are potent ferroptosis inducers.
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DOI：
10.1016/j.gendis.2022.10.016
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发表时间：
2023-05
期刊：
影响因子：
6.8
通讯作者：
Sun, Xiao-Jian
中科院分区：
文献类型：
--
作者：
Feng, Chang-Zhou;Li, Ning-Zhe;Hu, Xi-Bo;Xie, Yin -Yin;Huang, Qiu-Hua;Zhang, Jianming;Chen, Zhu;Chen, Sai-Juan;Wang, Fudi;Sun, Xiao-Jian
铁凋亡是一种受调节的细胞死亡形式，其特征在于铁依赖性脂质过氧化物过度积累，其导致膜损伤和细胞溶解。细胞抗氧化机制如谷胱甘肽过氧化物酶4（GPX 4）介导的以谷胱甘肽（GSH）为代价消除脂质过氧化物可预防铁凋亡。作为GSH合成的限速步骤，细胞内胱氨酸的可用性由位于细胞膜上的胱氨酸/谷氨酸反向转运体系统xc −控制。事实上，最初鉴定的铁凋亡小分子诱导剂RSL 3和erastin分别被证明是GPX 4和系统x c−的抑制剂。1，2自从最初被发现是RAS突变癌细胞的一种特性以来，铁凋亡已被证明受几种癌基因和肿瘤抑制因子的调节。LIFR是多效性细胞因子白血病抑制因子（LIF）的跨膜受体，最近已被证明是铁凋亡所必需的，因为小鼠肝肿瘤中Lifr基因的缺失赋予对铁凋亡的抗性。3有趣的是，在本研究中，我们发现靶向LIFR的小分子EC 330和EC 359是有效的铁凋亡诱导剂。EC 330/EC 359是设计成在配体-受体复合物内的两个相互作用界面之一（“位点3”）处结合LIFR的留体分子（图1A）。4 EC 330/EC 359可抑制LIF诱导的STAT 3和AKT通路的激活，并导致细胞死亡，与LIF和LIFR的表达水平相关。4然而，EC 330/EC 359是否能抑制LIFR的全部生物学功能尚不清楚，并且EC 330/EC 359诱导的细胞死亡尚未完全表征。在这方面，考虑到最近报道的LIFR在铁凋亡中的积极作用，3我们将EC 330/EC 359鉴定为铁凋亡诱导剂（而不是抑制剂）表明EC 330/EC 359通过不仅仅作为LIFR抑制剂的机制诱导铁凋亡的可能性。
Ferroptosis is a form of regulated cell death characterized by iron-dependent overaccumulation of lipid peroxides, which causes membrane damage and cell lysis. Ferroptosis can be prevented by cellular antioxidant mechanisms such as glutathione peroxidase 4 (GPX4)-mediated elimination of the lipid peroxides at the cost of glutathione (GSH). As the rate-limiting step of GSH synthesis, the availability of intracellular cystine is controlled by the cell membrane-located cystine/glutamate antiporter system x c−. Indeed, the initially identified small molecule inducers of ferroptosis, RSL3 and erastin, turned out to be inhibitors of GPX4 and system x c−, respectively. 1, 2Since originally being discovered as a property of RAS-mutant cancer cells, ferroptosis has been shown to be regulated by several oncogenes and tumor suppressors. LIFR, the transmembrane receptor of the pleiotropic cytokine leukemia inhibitory factor (LIF), has recently been shown to be required for ferroptosis, as loss of Lifr gene in mouse liver tumor confers resistance to ferroptosis. 3 Interestingly, in the present study, we found that the LIFR-targeting small molecules, EC330 and EC359, are potent ferroptosis inducers. EC330/EC359 are steroidal molecules designed to bind to LIFR at one (the “site 3”) of two interacting interfaces within the ligand-receptor complex (Fig. 1 A). 4 EC330/EC359 can suppress LIF-induced activation of STAT3 and AKT pathways and cause cell death correlated with the expression levels of LIF and LIFR in the cells. 4 However, it is unclear whether EC330/EC359 could inhibit the whole biological functions of LIFR, and the EC330/EC359-induced cell death has not been fully characterized. In this regard, given the recently reported positive role of LIFR in ferroptosis, 3 our identification of EC330/EC359 as ferroptosis inducers (instead of inhibitors) suggests a possibility that EC330/EC359 induce ferroptosis through a mechanism (s) beyond simply acting as inhibitors of LIFR.
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影响因子：
64.5
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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