Helicobacter pylori promotes gastric cancer progression by upregulating EPS8L3 to inhibit ferroptosis

doi:10.3748/wjg.119744

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Aug 28, 2026; 32(32): 119744
Published online Aug 28, 2026. doi: 10.3748/wjg.119744

Helicobacter pylori promotes gastric cancer progression by upregulating EPS8L3 to inhibit ferroptosis

Meng-Di Ma, Wan-Jing Chen, Ke-Xun Yu, Hui-Zhen Wang, Yong-Xiang Li

Meng-Di Ma, Wan-Jing Chen, Ke-Xun Yu, Hui-Zhen Wang, Yong-Xiang Li, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China

Wan-Jing Chen, Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China

Co-first authors: Meng-Di Ma and Wan-Jing Chen.

Author contributions: Li YX and Ma MD conceptualized and designed the research; Chen WJ screened patients and acquired clinical data; Ma MD wrote the paper; Yu KX and Wang HZ proposed, designed, and performed data analysis; Ma MD and Chen WJ were responsible for patient screening, enrollment, collection of clinical data and tissue specimens. Both authors have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper. All authors have read and approved the manuscript.

Supported by National Natural Science Foundation of China, No. 82372646; and Key Project of Scientific Research Project of Anhui Provincial Department of Education, China, No. 2023AH053334.

Institutional review board statement: The study was reviewed and approved by the Anhui Medical University Institutional Review Board, No. 20180323.

Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Anhui Medical University, No. 20180345.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: Data supporting the conclusions of this article are available upon request to the corresponding author, subject to applicable legal and ethical restrictions.

Corresponding author: Yong-Xiang Li, MD, Chief, Professor, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Shushan District, Hefei 230022, Anhui Province, China. liyongxiang@ahmu.edu.cn

Received: February 5, 2026
Revised: March 9, 2026
Accepted: April 28, 2026
Published online: August 28, 2026
Processing time: 179 Days and 18.5 Hours

Abstract

BACKGROUND

Gastric cancer (GC) represents one of the most prevalent malignancies globally and is ranked as the fourth leading cause of cancer-related mortality. Helicobacter pylori (H. pylori) infection is a major risk factor for GC, however, the molecular mechanisms by which H. pylori promotes gastric carcinogenesis remain unclear.

AIM

To investigate how H. pylori promotes GC development by activating specific signaling pathways.

METHODS

Transcriptome sequencing identified epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3) as highly expressed in GC cells co-cultured with H. pylori, which was further validated experimentally. Lentiviral knockdown or overexpression was used to assess its effects on GC cell proliferation, invasion, and migration. Ferroptosis was analyzed by flow cytometry. Nuclear factor kappa-B (NF-κB) was predicted as the upstream transcription factor using bioinformatics, and a nude mouse xenograft model evaluated the role of EPS8L3 in vivo.

RESULTS

H. pylori infection increased EPS8L3 expression in gastric epithelial and GC cells via activating NF-κB. Overexpression EPS8L3 enhanced GC cell proliferation, invasion, migration, and tumorigenicity, whereas EPS8L3 knockdown exerted the opposite effects. Mechanistically, EPS8L3 inhibited ferroptosis in GC cells by regulating glutathione metabolism and maintaining the stability of glutathione peroxidase 4 and solute carrier family 7 member 11. Inhibition of NF-κB reduced EPS8L3 expression and attenuated the malignant phenotype of GC cells.

CONCLUSION

H. pylori promotes gastric carcinogenesis and progression via activating the NF-κB/EPS8L3 pathway, which suppresses ferroptosis in GC cells. EPS8L3 may represent a potential therapeutic target for GC.

Keywords: Gastric cancer; Ferroptosis; Helicobacter pylori; Digestion; Nuclear factor kappa B

Core Tip: In this study, Helicobacter pylori co-cultured with the stomach cancer cell line AGS was subjected to transcriptome sequencing. The findings showed that Helicobacter pylori increase the transcription of epidermal growth factor receptor pathway substrate 8-like protein 3 via activating the nuclear factor kappa B signaling pathway. By participating in glutathione metabolism and interacting with solute carrier family 7 member 11 and glutathione peroxidase 4, epidermal growth factor receptor pathway substrate 8-like protein 3 plays a crucial function in preventing ferroptosis in gastric cancer. This process promotes the growth and spread of stomach cancer.