Deciphering the role of the MALT1–RC3H1 axis in regulating GPX4 protein stability
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.
Authors
- Guang‐Zhi Jin (ORCID: https://orcid.org/0000-0001-8961-4196)
- Botai Li
- Chong Sun (ORCID: https://orcid.org/0000-0001-9008-2158)
- Jia He (ORCID: https://orcid.org/0000-0002-2338-9501)
- René Bernards (ORCID: https://orcid.org/0000-0001-8677-3423)
- Wenxin Qin (ORCID: https://orcid.org/0000-0002-1989-3027)
- Shuyi Ji (ORCID: https://orcid.org/0009-0002-5348-1234)
- Long Liao (ORCID: https://orcid.org/0000-0002-9150-2377)
- Annika Fitz
- Qianqian Zhang (ORCID: https://orcid.org/0000-0001-8917-8523)
- Jun Wang (ORCID: https://orcid.org/0000-0001-5895-1333)
- Jianming Zhang (ORCID: https://orcid.org/0000-0001-6326-3906)
- Bo Yang (ORCID: https://orcid.org/0000-0002-9221-2144)
- Hui Wang (ORCID: https://orcid.org/0000-0002-5703-8574)
- Ying Cao (ORCID: https://orcid.org/0000-0002-5659-3146)
- Cun Wang (ORCID: https://orcid.org/0000-0002-4977-2189)
- Beiping Miao (ORCID: https://orcid.org/0000-0003-2307-3280)
- Xuhui Ma
- Shanshan Wu (ORCID: https://orcid.org/0000-0001-6417-8340)
Institutions
- Tongji University (CN)
- University of Science and Technology of China (CN)
- German Cancer Research Center (DE)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Renji Hospital (CN)
- Ruijin Hospital (CN)
- The Netherlands Cancer Institute (NL)
- Tongren Hospital (CN)
- Shanghai Cancer Institute (CN)
- Oncode Institute (NL)
- Zhongshan Hospital (CN)
- Shanghai Tenth People's Hospital (CN)
- Immune Regulation (United Kingdom) (GB)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-12-31
- DOI
- https://doi.org/10.1073/pnas.2419625121
- Citations
- 12
- Primary Topic
- Nitric Oxide and Endothelin Effects
- Type
- article
- Field-Weighted Citation Impact
- 3.92
Funders
- Natural Science Foundation of Shanghai
- Deutsches Krebsforschungszentrum
- National Natural Science Foundation of China
- Fudan University
- Shanghai Municipal Education Commission
- Tongji University
- Shanghai Jiao Tong University
- University of Science and Technology of China
- Ruijin Hospital
- Renji Hospital
- Oncode Institute
- School of Medicine, Shanghai Jiao Tong University
- National Natural Science Foundation of China-Guangdong Joint Fund