EIF3I reprograms iron metabolism to promote gastric cancer progression by stabilizing YAP
5 affiliations
- 1Laboratory of Molecular Target Therapy of Cancer, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei China
- 2Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei China
- 3Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang China
- 4Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei China
- 5Gucheng People’s Hospital, Hubei University of Arts and Science, Xiangyang, Hubei China
Abstract
Background: Although dysregulation of iron metabolism is known to contribute to tumorigenesis, the upstream mechanisms driving iron overload in gastric cancer (GC) remain poorly understood. This research aims to elucidate the oncogenic role of eukaryotic translation initiation factor 3 subunit I (EIF3I) in GC and its impact on iron metabolism.
Methods: EIF3I expression in GC was evaluated using clinical tissue samples and correlated with clinicopathological features. The functional impact of EIF3I on tumor progression was evaluated through both in vitro and in vivo assays. Molecular mechanisms were investigated using protein interaction studies, ubiquitination assays, and transcriptional analyses. A therapeutic peptide targeting EIF3I– was screened and tested in zebrafish and mice models.
Results: EIF3I was significantly overexpressed in GC and associated with aggressive tumor phenotypes. EIF3I depletion suppressed GC cell proliferation and tumor growth, while its overexpression enhanced malignancy. Mechanistically, EIF3I stabilized yes-associated protein 1 (YAP) by directly interacting with it and preventing its ubiquitination and degradation by STUB1. This stabilization promoted YAP nuclear liquid–liquid phase separation and transcriptional activity, leading to increased expression of transferrin receptor 1 (TFR1), and consequent intracellular iron accumulation. Targeting the EIF3I interface on YAP with a screened peptide restored STUB1-mediated YAP degradation and significantly inhibited tumor growth in vitro and in vivo.
Conclusions: EIF3I promotes GC progression by stabilizing YAP and reprogramming iron metabolism through the EIF3I–YAP-iron axis. Targeting this interaction represents a promising therapeutic strategy for GC.
Supplementary information: The online version contains supplementary material available at https://doi.org/10.1186/s11658-026-00987-9.
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BibTeX
@article{si2026eif3i,
title = {{EIF3I reprograms iron metabolism to promote gastric cancer progression by stabilizing YAP}},
author = {Yuan Si and Dan Yang and Haitao Zhang and Sicheng Wang and Liang Zhang and Xiu Shen and Kangrui Zhang and Ke Xiang and Xiangrong Zhan and Xu Zhang and Qingqing Yu and Xuewen Liu and Ying Liu},
journal = {Cellular \& Molecular Biology Letters},
year = {2026},
month = jul,
doi = {10.1186/s11658-026-00987-9},
url = {https://doi.org/10.1186/s11658-026-00987-9},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - EIF3I reprograms iron metabolism to promote gastric cancer progression by stabilizing YAP
AU - Yuan Si
AU - Dan Yang
AU - Haitao Zhang
AU - Sicheng Wang
AU - Liang Zhang
AU - Xiu Shen
AU - Kangrui Zhang
AU - Ke Xiang
AU - Xiangrong Zhan
AU - Xu Zhang
AU - Qingqing Yu
AU - Xuewen Liu
AU - Ying Liu
PY - 2026
DA - 2026/07/25
JO - Cellular & Molecular Biology Letters
DO - 10.1186/s11658-026-00987-9
UR - https://doi.org/10.1186/s11658-026-00987-9
AB - Background: Although dysregulation of iron metabolism is known to contribute to tumorigenesis, the upstream mechanisms driving iron overload in gastric cancer (GC) remain poorly understood. This research aims to elucidate the oncogenic role of eukaryotic translation initiation factor 3 subunit I (EIF3I) in GC and its impact on iron metabolism. Methods: EIF3I expression in GC was evaluated using clinical tissue samples and correlated with clinicopathological features. The functional impact of EIF3I on tumor progression was evaluated through both in vitro and in vivo assays. Molecular mechanisms were investigated using protein interaction studies, ubiquitination assays, and transcriptional analyses. A therapeutic peptide targeting EIF3I– was screened and tested in zebrafish and mice models. Results: EIF3I was significantly overexpressed in GC and associated with aggressive tumor phenotypes. EIF3I depletion suppressed GC cell proliferation and tumor growth, while its overexpression enhanced malignancy. Mechanistically, EIF3I stabilized yes-associated protein 1 (YAP) by directly interacting with it and preventing its ubiquitination and degradation by STUB1. This stabilization promoted YAP nuclear liquid–liquid phase separation and transcriptional activity, leading to increased expression of transferrin receptor 1 (TFR1), and consequent intracellular iron accumulation. Targeting the EIF3I interface on YAP with a screened peptide restored STUB1-mediated YAP degradation and significantly inhibited tumor growth in vitro and in vivo. Conclusions: EIF3I promotes GC progression by stabilizing YAP and reprogramming iron metabolism through the EIF3I–YAP-iron axis. Targeting this interaction represents a promising therapeutic strategy for GC. Supplementary information: The online version contains supplementary material available at https://doi.org/10.1186/s11658-026-00987-9.
SN - 1425-8153
SN - 1689-1392
ER -