TY  - JOUR
AU  - Wang, Jun
AU  - Liao, Long
AU  - Miao, Beiping
AU  - Yang, Bo
AU  - Li, Botai
AU  - Ma, Xuhui
AU  - Fitz, Annika
AU  - Wu, Shanshan
AU  - He, Jia
AU  - Zhang, Qianqian
AU  - Ji, Shuyi
AU  - Jin, Guangzhi
AU  - Zhang, Jianming
AU  - Cao, Ying
AU  - Wang, Hui
AU  - Qin, Wenxin
AU  - Sun, Chong
AU  - Bernards, René
AU  - Wang, Cun
TI  - Deciphering the role of the MALT1-RC3H1 axis in regulating GPX4 protein stability.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 122
IS  - 1
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DKFZ-2025-00034
SP  - e2419625121
PY  - 2025
N1  - #EA:D250#
AB  - 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.
KW  - Humans
KW  - Phospholipid Hydroperoxide Glutathione Peroxidase: metabolism
KW  - Phospholipid Hydroperoxide Glutathione Peroxidase: genetics
KW  - Ferroptosis: genetics
KW  - Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein: metabolism
KW  - Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein: genetics
KW  - Protein Stability
KW  - Ubiquitin-Protein Ligases: metabolism
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Sorafenib: pharmacology
KW  - Cell Line, Tumor
KW  - Ubiquitination
KW  - Liver Neoplasms: metabolism
KW  - Liver Neoplasms: genetics
KW  - Liver Neoplasms: drug therapy
KW  - Liver Neoplasms: pathology
KW  - Phenylurea Compounds: pharmacology
KW  - Gene Expression Regulation, Neoplastic
KW  - Pyridines
KW  - GPX4 (Other)
KW  - MALT1 (Other)
KW  - ferroptosis (Other)
KW  - liver cancer (Other)
KW  - Phospholipid Hydroperoxide Glutathione Peroxidase (NLM Chemicals)
KW  - Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - MALT1 protein, human (NLM Chemicals)
KW  - Sorafenib (NLM Chemicals)
KW  - regorafenib (NLM Chemicals)
KW  - Phenylurea Compounds (NLM Chemicals)
KW  - Pyridines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39739814
DO  - DOI:10.1073/pnas.2419625121
UR  - https://inrepo02.dkfz.de/record/296086
ER  -