USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy
成果类型：
Article
署名作者：
Li, Haiou; Sun, Yishuang; Yao, Yingmeng; Ke, Shanwen; Zhang, Nannan; Xiong, Wenjun; Shi, Jie; He, Chuan; Xiao, Xiangling; Yu, Haisheng; Dai, Panpan; Xiang, Bolin; Xing, Xixin; Xu, Gaoshan; Song, Wenjing; Song, Jiquan; Zhang, Jinfang
署名单位：
Wuhan University; Wuhan University; Zhengzhou University; Zhengzhou University; Wuhan University; Wuhan University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-10484
DOI：
10.1073/pnas.2315541121
发表日期：
2024-04-16
关键词：
glutathione-peroxidase 4
protease usp8
ubiquitin
deficiency
GROWTH
death
摘要：
Ferroptosis is an iron- dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin- specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to antiPD - 1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.