Deciphering the role of the MALT1-RC3H1 axis in regulating GPX4 protein stability

• 成果类型: Article
• 署名作者: Wang, Jun; Liao, Long; Miao, Beiping; Yang, Bo; Li, Botai; Ma, Xuhui; Fitz, Annika; Wu, Shanshan; He, Jia; Zhang, Qianqian; Ji, Shuyi; Jin, Guangzhi; Zhang, Jianming; Cao, Ying; Wang, Hui; Qin, Wenxin; Sun, Chong; Bernardsa, Rene; Wang, Cun
• 署名单位: Shanghai Jiao Tong University; Helmholtz Association; German Cancer Research Center (DKFZ); Chinese Academy of Sciences; University of Science & Technology of China, CAS; Shanghai Jiao Tong University; Netherlands Cancer Institute; Tongji University; Chinese Academy of Sciences; Shanghai Jiao Tong University; Fudan University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Netherlands Cancer Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9024
• DOI: 10.1073/pnas.2419625121
• 发表日期: 2025-01-07
• 关键词: hepatocellular-carcinoma; ubiquitin ligase; cancer-cells; DOUBLE-BLIND; sorafenib; ferroptosis; regorafenib; malt1; death

摘要

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.