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000296086 1001_ $$aWang, Jun$$b0
000296086 245__ $$aDeciphering the role of the MALT1-RC3H1 axis in regulating GPX4 protein stability.
000296086 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2025
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000296086 520__ $$aFerroptosis, a unique form of iron-dependent cell death triggered by lipid peroxidation accumulation, holds great promise for cancer therapy. Despite the crucial role of GPX4 in regulating ferroptosis, our understanding of GPX4 protein regulation remains limited. Through FACS-based genome-wide CRISPR screening, we identified MALT1 as a regulator of GPX4 protein. Inhibition of MALT1 expression enhances GPX4 ubiquitination-mediated degradation by up-regulating the E3 ubiquitin ligase RC3H1. Using both rescue assays and functional genetic screening, we demonstrate that pharmacologically targeting MALT1 triggers ferroptosis in liver cancer cells. Moreover, we show that targeting MALT1 synergizes with sorafenib or regorafenib to induce ferroptosis across multiple cancer types. These findings elucidate the modulatory effects of the MALT1-RC3H1 axis on GPX4 stability, revealing a molecular mechanism that could be exploited to induce ferroptosis for cancer therapy.
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000296086 650_7 $$2Other$$aGPX4
000296086 650_7 $$2Other$$aMALT1
000296086 650_7 $$2Other$$aferroptosis
000296086 650_7 $$2Other$$aliver cancer
000296086 650_7 $$0EC 1.11.1.12$$2NLM Chemicals$$aPhospholipid Hydroperoxide Glutathione Peroxidase
000296086 650_7 $$0EC 3.4.22.-$$2NLM Chemicals$$aMucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
000296086 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aUbiquitin-Protein Ligases
000296086 650_7 $$0EC 3.4.22.-$$2NLM Chemicals$$aMALT1 protein, human
000296086 650_7 $$09ZOQ3TZI87$$2NLM Chemicals$$aSorafenib
000296086 650_7 $$024T2A1DOYB$$2NLM Chemicals$$aregorafenib
000296086 650_7 $$2NLM Chemicals$$aPhenylurea Compounds
000296086 650_7 $$2NLM Chemicals$$aPyridines
000296086 650_2 $$2MeSH$$aHumans
000296086 650_2 $$2MeSH$$aPhospholipid Hydroperoxide Glutathione Peroxidase: metabolism
000296086 650_2 $$2MeSH$$aPhospholipid Hydroperoxide Glutathione Peroxidase: genetics
000296086 650_2 $$2MeSH$$aFerroptosis: genetics
000296086 650_2 $$2MeSH$$aMucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein: metabolism
000296086 650_2 $$2MeSH$$aMucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein: genetics
000296086 650_2 $$2MeSH$$aProtein Stability
000296086 650_2 $$2MeSH$$aUbiquitin-Protein Ligases: metabolism
000296086 650_2 $$2MeSH$$aUbiquitin-Protein Ligases: genetics
000296086 650_2 $$2MeSH$$aSorafenib: pharmacology
000296086 650_2 $$2MeSH$$aCell Line, Tumor
000296086 650_2 $$2MeSH$$aUbiquitination
000296086 650_2 $$2MeSH$$aLiver Neoplasms: metabolism
000296086 650_2 $$2MeSH$$aLiver Neoplasms: genetics
000296086 650_2 $$2MeSH$$aLiver Neoplasms: drug therapy
000296086 650_2 $$2MeSH$$aLiver Neoplasms: pathology
000296086 650_2 $$2MeSH$$aPhenylurea Compounds: pharmacology
000296086 650_2 $$2MeSH$$aGene Expression Regulation, Neoplastic
000296086 650_2 $$2MeSH$$aPyridines
000296086 7001_ $$aLiao, Long$$b1
000296086 7001_ $$0P:(DE-He78)b5b786a7a28d851956ba90aa9451887a$$aMiao, Beiping$$b2$$eFirst author$$udkfz
000296086 7001_ $$aYang, Bo$$b3
000296086 7001_ $$aLi, Botai$$b4
000296086 7001_ $$aMa, Xuhui$$b5
000296086 7001_ $$0P:(DE-He78)0d8fa784ae0ac78e2f5ef9159c0dc608$$aFitz, Annika$$b6$$udkfz
000296086 7001_ $$aWu, Shanshan$$b7
000296086 7001_ $$aHe, Jia$$b8
000296086 7001_ $$aZhang, Qianqian$$b9
000296086 7001_ $$aJi, Shuyi$$b10
000296086 7001_ $$aJin, Guangzhi$$b11
000296086 7001_ $$aZhang, Jianming$$b12
000296086 7001_ $$aCao, Ying$$b13
000296086 7001_ $$aWang, Hui$$b14
000296086 7001_ $$aQin, Wenxin$$b15
000296086 7001_ $$0P:(DE-He78)ef40d75e5564c492ee57b4262fc016fe$$aSun, Chong$$b16$$udkfz
000296086 7001_ $$00000-0001-8677-3423$$aBernards, René$$b17
000296086 7001_ $$00000-0002-4977-2189$$aWang, Cun$$b18
000296086 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.2419625121$$gVol. 122, no. 1, p. e2419625121$$n1$$pe2419625121$$tProceedings of the National Academy of Sciences of the United States of America$$v122$$x0027-8424$$y2025
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