ID4 enhances ferroptosis sensitivity in gastric cancer by promoting ubiquitination degradation of GPX4.
6 affiliations
- 1Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, 250013, People's Republic of China.
- 2Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, 56# shanda south road, Jinan, 250013, Shandong Province, P. R. China.
- 3Department of Medical Laboratory, Shandong Second Medical University, Weifang, 261053, People's Republic of China.
- 4Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, 250013, People's Republic of China. [email protected].
- 5Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, 56# shanda south road, Jinan, 250013, Shandong Province, P. R. China. [email protected].
- 6Department of Medical Laboratory, Shandong Second Medical University, Weifang, 261053, People's Republic of China. [email protected].
Abstract
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.
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BibTeX
@article{jing2026enhances,
title = {{ID4 enhances ferroptosis sensitivity in gastric cancer by promoting ubiquitination degradation of GPX4.}},
author = {Fubo Jing and Wenshuai Zhu and He Qi and Yuanxin Xing and Yuxuan Shi and Xiaoli Ma and Yunshan Wang and Yanfei Jia},
journal = {Cellular and molecular life sciences : CMLS},
year = {2026},
month = aug,
doi = {10.1007/s00018-026-06373-0},
url = {https://europepmc.org/article/MED/42957865},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - ID4 enhances ferroptosis sensitivity in gastric cancer by promoting ubiquitination degradation of GPX4.
AU - Fubo Jing
AU - Wenshuai Zhu
AU - He Qi
AU - Yuanxin Xing
AU - Yuxuan Shi
AU - Xiaoli Ma
AU - Yunshan Wang
AU - Yanfei Jia
PY - 2026
DA - 2026/08/04
JO - Cellular and molecular life sciences : CMLS
DO - 10.1007/s00018-026-06373-0
UR - https://europepmc.org/article/MED/42957865
AB - 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.
SN - 1420-682X
SN - 1420-9071
ER -