[煎剂通过促进细胞铁死亡——P53/SLC7A11/GPX4轴抑制胃癌细胞异种移植瘤生长]
[ Decoction inhibits growth of gastric cancer cell xenografts by promoting cell ferroptosis the P53/SLC7A11/GPX4 axis].
作者信息
Chen Xinyuan, Wu Chengting, Li Ruidi, Pan Xueqin, Zhang Yaodan, Tao Junyu, Lin Caizhi
机构信息
Guangxi University of Chinese Medicine, Nanning 530299, China.
Department of Spleen and Gastroenterology, Xianhu Campus of First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530200, China.
出版信息
Nan Fang Yi Ke Da Xue Xue Bao. 2025 Jul 20;45(7):1363-1371. doi: 10.12122/j.issn.1673-4254.2025.07.02.
OBJECTIVES
To explore the mechanism of Decoction (SSD) for inhibiting growth of gastric cancer xenografts in nude mice.
METHODS
Network pharmacology analysis was conducted to identify the common targets of SSD and gastric cancer cell ferroptosis, and bioinformatics analysis and molecular docking were used to validate the core targets. In the cell experiment, AGS cells were treated with SSD-medicated serum, Fer-1 (a ferroptosis inhibitor), or both, and the changes in cell viability, ferroptosis markers (ROS, Fe and GSH), expressions of P53, SLC7A11 and GPX4, and mitochondrial morphology were examined. In a nude mouse model bearing gastric cancer xenografts, the effects of gavage with SSD, intraperitoneal injection of Fer-1, or their combination on tumor volume/weight, histopathology, and expressions of P53, SLC7A11 and GPX4 levels were evaluated.
RESULTS
The active components in SSD (quercetin and wogonin) showed strong binding affinities to P53. In AGS cells, SSD treatment dose-dependently inhibited cell proliferation, increased ROS and Fe levels, upregulated P53 expression, and downregulated the expressions of SLC7A11 and GPX4, but these effects were effectively attenuated by Fer-1 treatment. SSD also induced mitochondrial shrinkage and increased the membrane density, which were alleviated by Fer-1. In the tumor-bearing mouse models, gavage with SSD significantly reduced tumor size and weight, caused tumor cell necrosis, upregulated P53 and downregulated SLC7A11 and GPX4 expression in the tumor tissue, and these effects were obviously mitigated by Fer-1 treatment.
CONCLUSIONS
SSD inhibits gastric cancer growth in nude mice by inducing cell ferroptosis via the P53/SLC7A11/GPX4 axis.
目的
探讨四神煎（SSD）抑制裸鼠胃癌异种移植瘤生长的机制。
方法
采用网络药理学分析确定SSD与胃癌细胞铁死亡的共同靶点，并运用生物信息学分析和分子对接验证核心靶点。细胞实验中，用SSD含药血清、Fer-1（一种铁死亡抑制剂）或两者处理AGS细胞，检测细胞活力、铁死亡标志物（ROS、Fe和GSH）、P53、SLC7A11和GPX4的表达变化以及线粒体形态。在荷胃癌异种移植瘤的裸鼠模型中，评估灌胃SSD、腹腔注射Fer-1或两者联合对肿瘤体积/重量、组织病理学以及P53、SLC7A11和GPX4水平表达的影响。
结果
SSD中的活性成分（槲皮素和汉黄芩素）与P53显示出较强的结合亲和力。在AGS细胞中，SSD处理呈剂量依赖性抑制细胞增殖，增加ROS和Fe水平，上调P53表达，下调SLC7A11和GPX4的表达，但这些作用被Fer-1处理有效减弱。SSD还诱导线粒体收缩并增加膜密度，而Fer-1可缓解这些变化。在荷瘤小鼠模型中，灌胃SSD显著减小肿瘤大小和重量，导致肿瘤细胞坏死，上调肿瘤组织中P53表达并下调SLC7A11和GPX4表达，且这些作用被Fer-1处理明显减轻。
结论
SSD通过P53/SLC7A11/GPX4轴诱导细胞铁死亡来抑制裸鼠胃癌生长。
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