Scholarlink

<p>Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide, presenting a serious threat to human health due to its high fatality rates and incidence. Ferroptosis, as a novel form of programmed cell death, demonstrates significant potential in cancer therapy. The mechanisms underlying ferroptosis sensitivity in GC is crucial for developing novel therapeutic strategies. Our findings reveal that the tumor suppressor gene ID4 enhances the sensitivity of GC cells to ferroptosis by increasing the ubiquitin-mediated degradation of GPX4 in gastric cancer cell lines, mouse models, and patient-derived tumor organoids. Mechanistically, ID4 interacts with the bHLH family transcription factor TCF3, inhibiting its transcription of USP2. Downregulation of USP2 expression increases the ubiquitination level of GPX4, promoting its ubiquitin-mediated degradation. This leads to increased ROS accumulation within GC cells and heightened sensitivity to ferroptosis. In vivo experiments demonstrated that ID4 overexpression significantly enhanced the tumor-suppressing effects of RSL3, with even more pronounced suppression observed when combined with the USP2 inhibitor PR-619. This study identifies ID4 as a key regulator in ferroptosis resistance during GC progression. The therapeutic strategy of targeting ID4 alongside ferroptosis inducers may pave the way for overcoming drug resistance in refractory GC.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

ID4 enhances ferroptosis sensitivity in gastric cancer by promoting ubiquitination degradation of GPX4

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月4日

查看全文
  • Fubo Jing,
  • Wenshuai Zhu,
  • He Qi,
  • Yuanxin Xing,
  • Yuxuan Shi,
  • Xiaoli Ma,
  • Yunshan Wang,
  • Yanfei Jia

摘要

Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide, presenting a serious threat to human health due to its high fatality rates and incidence. Ferroptosis, as a novel form of programmed cell death, demonstrates significant potential in cancer therapy. The mechanisms underlying ferroptosis sensitivity in GC is crucial for developing novel therapeutic strategies. Our findings reveal that the tumor suppressor gene ID4 enhances the sensitivity of GC cells to ferroptosis by increasing the ubiquitin-mediated degradation of GPX4 in gastric cancer cell lines, mouse models, and patient-derived tumor organoids. Mechanistically, ID4 interacts with the bHLH family transcription factor TCF3, inhibiting its transcription of USP2. Downregulation of USP2 expression increases the ubiquitination level of GPX4, promoting its ubiquitin-mediated degradation. This leads to increased ROS accumulation within GC cells and heightened sensitivity to ferroptosis. In vivo experiments demonstrated that ID4 overexpression significantly enhanced the tumor-suppressing effects of RSL3, with even more pronounced suppression observed when combined with the USP2 inhibitor PR-619. This study identifies ID4 as a key regulator in ferroptosis resistance during GC progression. The therapeutic strategy of targeting ID4 alongside ferroptosis inducers may pave the way for overcoming drug resistance in refractory GC.