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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells
Chu-Xuan Liu, Ying Gao, Xiu-Fang Xu, Xin Jin, Yun Zhang, Qian Xu, Huan-Xin Ding, Bing-Jun Li, Fang-Ke Du, Lin-Chuan Li, Ming-Wei Zhong, Jian-Kang Zhu, Guang-Yong Zhang
Chu-Xuan Liu, Xin Jin, Guang-Yong Zhang, Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong Province, China
Ying Gao, Department of General Surgery, Linyi People's Hospital, Linyi 276034, Shandong Province, China
Xiu-Fang Xu, Department of Nursing, Huantai TCM Hospital, Zibo 256400, Shandong Province, China
Yun Zhang, Center for Translational medical Research, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong Province, China
Qian Xu, Huan-Xin Ding, Bing-Jun Li, Fang-Ke Du, Lin-Chuan Li, Ming-Wei Zhong, Jian-Kang Zhu, Guang-Yong Zhang, Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong Province, China
Author contributions: Zhong MW, Zhu JK and Zhang GY designed and coordinated the study; Liu CX, Gao Y, Jin X and Zhang Y performed the experiments, acquired and analyzed data; Liu CX, Xu Q and Ding HX, interpreted the data; Liu CX, Li BJ, Du FK, Li LC and Zhang GY wrote the manuscript; Xu XF revised this study; all authors approved the final version of the article.
Supported by the Major Basic Research Project of Natural Science Foundation of Shandong Province, No. ZR2020ZD15.
Institutional review board statement: This basic study did not involve human and/or animal subjects.
Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Guang-Yong Zhang, MD, Chief Doctor, Professor, Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, No. 16766 Jingshi Road, Jinan 250014, Shandong Province, China. guangyongzhang@hotmail.com
Received: November 21, 2023
Peer-review started: November 21, 2023
First decision: December 8, 2023
Revised: December 12, 2023
Accepted: January 11, 2024
Article in press: January 11, 2024
Published online: February 7, 2024
ARTICLE HIGHLIGHTS
Research background
Gastric cancer (GC) is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths because of the difficulties associated with early diagnosis. Bile acids (BAs) reflux, as an etiologic factor for GC, is receiving more attentions. BAs are engaged in the regulation of metabolism, and the latter is closely related to the ferroptosis. Thus BAs may be potentially relevant to the regulation of ferroptosis.
Research motivation
To elaborate the relationship between BAs and ferroptosis in GC and to providing new insights into the precise treatment of GC patients with BAs reflux.
Research objectives
In this study, we aimed to explore the role of BAs in regulating ferroptosis in GC and to investigate the underlying molecular mechanisms. The present study helps to further elucidate the pathophysiologic mechanisms in GC patients with BAs reflux.
Research methods
The research methods are as follows: cell transfection, cell viability assay, glutathione (GSH) and Malondialdehyde assay quantification, lipid reactive oxygen species assay, 5-ethynyl-2′-deoxyuridine staining, colony formation assay, Western blot.
Research results
Firstly, we found that BAs can promote GC cell proliferation and inhibit erastin-induced ferroptosis sensitivity through upregulate GSH and GSH peroxidase 4 (GPX4). Secondly, BAs exerted its anti-ferroptosis sensitivity function in GC cells by activating farnesoid X receptor (FXR) which significantly promoted GSH synthesis. Subsequently, BTB and CNC homology 1 (BACH1) provided an essential bridging role in BAs and FXR facilitating GSH synthesis. Finally, the notable oncogenic effects of FXR were discovered.
Research conclusions
BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSH-GPX4 axis in GC cells.
Research perspectives
The findings of this basic study will be validated in in vivo experiments and clinical specimens to clarify whether FXR and BACH1 can serve as therapeutic targets for GC patients with BAs reflux.
