通过ATF4/GSH/GPX4轴介导的铁毒性诱导的酸乙毒性
Chen Xi1, Jie Zhou2, Xin Zheng3
1Pharmaceutical Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.
Scientific reports
|January 8, 2025
概括
酸 (SA) 通过诱导细胞死亡的一种形式铁亡,导致肝损伤. 这是因为SA抑制了激活转录因子4 (ATF4),破坏了细胞抗氧化防御,导致氧化损伤.
科学领域:
- 生物化学 生物化学
- 毒理学 毒理学 毒理学
- 细胞生物学 细胞生物学
背景情况:
- 酸 (SA) 是一种用于治疗和炎症的植物提取物.
- 酸盐与包括肝损伤在内的不良事件有关.
研究的目的:
- 为了研究铁质在酸诱导的肝损伤中的作用.
- 阐明SA诱导的肝毒性背后的分子机制.
主要方法:
- 使用BALB/c小鼠进行体内研究,以评估肝功能和病理.
- 使用L02细胞进行体外研究以评估细胞活力和铁亡标志物.
- 对激活转录因子4 (ATF4) 和其下游目标 (xCT,CTH) 的分析.
主要成果:
- 在体内增加了SA肝酶 (AST,ALT),MDA和Fe2+,同时降低了GSH.
- 在L02细胞中,SA诱导了铁亡,由降低活力,LDH释放,GSH枯竭,铁积累,ROS产生和脂质过氧化证明.
- SA抑制了ATF4的转录活性,导致xCT和CTH的表达减少,这对于GSH合成至关重要.
- ATF4过度表达减轻了SA的细胞毒性,而ATF4沉默则加剧了它.
结论:
- 乙酸通过抑制ATF4活性来触发肝细胞铁亡.
- 这种抑制会破坏GSH生物合成途径,导致氧化失衡和肝损伤.
- 铁死在SA的不良肝脏影响中起着重要作用.
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