Bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells

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.