Journal Article

DKFZ-2025-00034

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Deciphering the role of the MALT1-RC3H1 axis in regulating GPX4 protein stability.

Wang, J. ; Liao, L. ; Miao, B. (First author)DKFZ* ; Yang, B. ; Li, B. ; Ma, X. ; Fitz, A.DKFZ* ; Wu, S. ; He, J. ; Zhang, Q. ; Ji, S. ; Jin, G. ; Zhang, J. ; Cao, Y. ; Wang, H. ; Qin, W. ; Sun, C.DKFZ* ; Bernards, R. ; Wang, C.

2025
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: doi:10.1073/pnas.2419625121

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.

Keyword(s): Humans (MeSH) ; Phospholipid Hydroperoxide Glutathione Peroxidase: metabolism (MeSH) ; Phospholipid Hydroperoxide Glutathione Peroxidase: genetics (MeSH) ; Ferroptosis: genetics (MeSH) ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein: metabolism (MeSH) ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein: genetics (MeSH) ; Protein Stability (MeSH) ; Ubiquitin-Protein Ligases: metabolism (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Sorafenib: pharmacology (MeSH) ; Cell Line, Tumor (MeSH) ; Ubiquitination (MeSH) ; Liver Neoplasms: metabolism (MeSH) ; Liver Neoplasms: genetics (MeSH) ; Liver Neoplasms: drug therapy (MeSH) ; Liver Neoplasms: pathology (MeSH) ; Phenylurea Compounds: pharmacology (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Pyridines (MeSH) ; GPX4 ; MALT1 ; ferroptosis ; liver cancer ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; Ubiquitin-Protein Ligases ; MALT1 protein, human ; Sorafenib ; regorafenib ; Phenylurea Compounds ; Pyridines

Note: #EA:D250#

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Contributing Institute(s):

1. NWG Krebs-Immunregulation (D250)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; National-Konsortium ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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