Deciphering the role of the MALT1–RC3H1 axis in regulating GPX4 protein stability
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Jun Wang
Long Liao
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Beiping Miao
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Bo Yang
Botai Li
Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Xuhui Ma
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Annika Fitz
Shanshan Wu
College of Chemistry and Chemical Engineering, Frontiers Science Center for Rare Isotopes
Jia He
Qianqian Zhang
Shuyi Ji
Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University
Guangzhi Jin
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine
Jianming Zhang
Institute of Quantum and Sustainable Technology (IQST), School of Chemistry and Chemical Engineering
Ying Cao
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Hui Wang
Wenxin Qin
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Chong Sun
Division Immune Regulation in Cancer, German Cancer Research Center
René Bernards
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Cun Wang
State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Institute of Future Agriculture, Northwest A&F University