机构：[1]State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China[2]German Cancer Research Center, Division Immune Regulation in Cancer, Heidelberg 69120, Germany[3]Division of Reproduction and Genetics, First Affiliated Hospital of University of Science and Technology of China, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China[4]Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China[5]Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands[6]Department of Medical Oncology, Shanghai Tenth People’s Hospital, Tongji University, School of Medicine, Shanghai 200072, China[7]National Research Center for Translational Medicine (Shanghai), State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China[8]Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, China[9]Department of Interventional Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China[10]Institute of Translational Medicine, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China[11]Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
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.
基金：
National Natural Science Foundation of China [82473367, 82122047, 82072633, 82403136, 82330095, 81920108025, 82203044, 82003171, 82202062, 82303000, 21TQ1400225, 24X010301470]; Innovative research team of high-level local universities in Shanghai, Central University Outstanding Youth Team Cultivation Program [TMSK-2021-129]; Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20181703]; Shanghai Natural Science Foundation [22ZR1480900, 23YF1443400]
第一作者机构：[1]State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
共同第一作者：
通讯作者：
通讯机构：[1]State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China[11]Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
推荐引用方式(GB/T 7714)：
Wang Jun,Liao Long,Miao Beiping,et al.Deciphering the role of the MALT1-RC3H1 axis in regulating GPX4 protein stability[J].PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA.2025,122(1):doi:10.1073/pnas.2419625121.
APA：
Wang, Jun,Liao, Long,Miao, Beiping,Yang, Bo,Li, Botai...&Wang, Cun.(2025).Deciphering the role of the MALT1-RC3H1 axis in regulating GPX4 protein stability.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,122,(1)
MLA：
Wang, Jun,et al."Deciphering the role of the MALT1-RC3H1 axis in regulating GPX4 protein stability".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 122..1(2025)
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