Deciphering the role of the MALT1–RC3H1 axis in regulating GPX4 protein stability

IF 9.4 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Jun Wang, Long Liao, Beiping Miao, Bo Yang, Botai Li, Xuhui Ma, Annika Fitz, Shanshan Wu, Jia He, Qianqian Zhang, Shuyi Ji, Guangzhi Jin, Jianming Zhang, Ying Cao, Hui Wang, Wenxin Qin, Chong Sun, René Bernards, Cun Wang
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引用次数: 0

Abstract

Ferroptosis, a unique form of iron-dependent cell death triggered by lipid peroxidation accumulation, holds great promise for cancer therapy. Despite the crucial role of GPX4 in regulating ferroptosis, our understanding of GPX4 protein regulation remains limited. Through FACS-based genome-wide CRISPR screening, we identified MALT1 as a regulator of GPX4 protein. Inhibition of MALT1 expression enhances GPX4 ubiquitination-mediated degradation by up-regulating the E3 ubiquitin ligase RC3H1. Using both rescue assays and functional genetic screening, we demonstrate that pharmacologically targeting MALT1 triggers ferroptosis in liver cancer cells. Moreover, we show that targeting MALT1 synergizes with sorafenib or regorafenib to induce ferroptosis across multiple cancer types. These findings elucidate the modulatory effects of the MALT1–RC3H1 axis on GPX4 stability, revealing a molecular mechanism that could be exploited to induce ferroptosis for cancer therapy.
解读MALT1-RC3H1轴在调节GPX4蛋白稳定性中的作用
铁下垂是一种由脂质过氧化积累引发的铁依赖性细胞死亡的独特形式,在癌症治疗中具有很大的前景。尽管GPX4在调节铁下垂中起着至关重要的作用,但我们对GPX4蛋白调控的了解仍然有限。通过基于facs的全基因组CRISPR筛选,我们发现MALT1是GPX4蛋白的调节因子。抑制MALT1表达可通过上调E3泛素连接酶RC3H1增强GPX4泛素化介导的降解。通过抢救试验和功能基因筛选,我们证明了以MALT1为靶点的药物可触发肝癌细胞中的铁下垂。此外,我们发现靶向MALT1与索拉非尼或瑞非尼协同作用可诱导多种癌症类型的铁死亡。这些发现阐明了MALT1-RC3H1轴对GPX4稳定性的调节作用,揭示了一种可用于诱导铁凋亡以治疗癌症的分子机制。
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来源期刊
CiteScore
19.00
自引率
0.90%
发文量
3575
审稿时长
2.5 months
期刊介绍: The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.
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