Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 7, 2024; 30(5): 485-498
Published online Feb 7, 2024. doi: 10.3748/wjg.v30.i5.485
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
Abstract
BACKGROUND

Gastric cancer (GC) is associated with high mortality rates. Bile acids (BAs) reflux is a well-known risk factor for GC, but the specific mechanism remains unclear. During GC development in both humans and animals, BAs serve as signaling molecules that induce metabolic reprogramming. This confers additional cancer phenotypes, including ferroptosis sensitivity. Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression. However, it is not fully defined if BAs can influence GC progression by modulating ferroptosis.

AIM

To reveal the mechanism of BAs regulation in ferroptosis of GC cells.

METHODS

In this study, we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis. We used gain and loss of function assays to examine the impacts of farnesoid X receptor (FXR) and BTB and CNC homology 1 (BACH1) overexpression and knockdown to obtain further insights into the molecular mechanism involved.

RESULTS

Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells. This effect correlated with increased glutathione (GSH) concentrations, a reduced GSH to oxidized GSH ratio, and higher GSH peroxidase 4 (GPX4) expression levels. Subsequently, we confirmed that BAs exerted these effects by activating FXR, which markedly increased the expression of GSH synthetase and GPX4. Notably, BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR. Finally, our results suggested that FXR could significantly promote GC cell proliferation, which may be closely related to its anti-ferroptosis effect.

CONCLUSION

This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSH-GPX4 axis in GC cells. This work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.

Keywords: Gastric cancer, Ferroptosis, Bile acids, Chenodeoxycholic acid, Farnesoid X receptor, Glutathione

Core Tip: Gastric cancer (GC) is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths. Bile acids (BAs) reflux is an essential carcinogenic factor in GC, but its role has not been absolutely elaborated. BAs could serve as signaling molecules to regulate the metabolic state in cells, which is closely related to ferroptosis. In the present experiment, we explored the role of BAs in the regulation of ferroptosis in GC cells. Our data suggested that BAs could significantly inhibit the ferroptosis sensitivity of GC cells and that this effect was exerted through the activation of the farnesoid X receptor-BTB and CNC homology 1-glutathione (GSH)-GSH peroxidase 4 axis.