GPX4
法尼甾体X受体
谷胱甘肽
基因敲除
癌症研究
化学
癌细胞
细胞凋亡
生物
细胞生物学
癌症
生物化学
核受体
谷胱甘肽过氧化物酶
转录因子
遗传学
基因
酶
作者
Can Liu,Ying Gao,Xiufang Xu,Xin Jin,Yun Zhang,Qi Xu,Huanxin Ding,Bingjun Li,Du Fan,Linchuan Li,Mingwei Zhong,Jiankang Zhu,Guangyong Zhang
标识
DOI:10.3748/wjg.v30.i5.485
摘要
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.
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