Stat1/Nrf2通路在加剧crizotinib诱导的肝损伤中的参与:对铁亡的含义
Lin Guo1,2,3, JiaTing Ma1,2,3, MingXuan Xiao1,2,3
1Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.
Cell death & disease
|August 19, 2024
概括
克里佐提尼布可以通过细胞死亡途径铁死 (ferroptosis) 引起肝损伤. 研究人员发现,抑制铁亡和向Stat1/Nrf2通路可能会防止Crizotinib诱导的肝毒性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 肝病学 肝病学是一种肝病学.
背景情况:
- 克里佐替尼与FDA报告的肝毒性有关,但潜在的机制和潜在的干预措施尚未完全理解.
- 分析表明,严重的肝损伤,包括肝炎和肝衰竭,可能在FAERS数据库中被低估.
研究的目的:
- 为了阐明Crizotinib诱导的肝毒性机制.
- 为了确定潜在的治疗策略,以减轻Crizotinib诱导的肝损伤.
主要方法:
- 进行了mRNA测序,KEGG和基因本体学 (GO) 分析,以确定差异表达基因 (DEG).
- 在体内和体外的研究中使用了铁灭抑制剂 (费洛斯塔丁-1,德费洛胺甲基酸盐),AAV8介导的Nrf2过度表达,Stat1缺乏和Stat1抑制剂 (NSC118218).
- 研究了信号转换器和转录1 (Stat1) 化激活器的作用及其对核因子红色素2相关因子2 (Nrf2) 表达的影响.
主要成果:
- 铁亡被确定为由crizotinib诱导的肝细胞死亡的主要机制.
- 铁酶抑制剂和Nrf2过度表达显著降低了Crizotinib诱导的肝毒性.
- 克里佐替尼在Ser727 (而不是Tyr701) 中诱导了Stat1酸化,抑制了Nrf2表达并促进了铁亡.
- MgIG和GA通过抵消ferroptosis,可能通过Stat1/Nrf2通路,而不会影响Crizotinib的抗癌活性,从而防止肝毒性.
结论:
- 克里佐替尼诱导的肝毒性是由铁中介的,由Ser727的Stat1酸化驱动,导致Nrf2转录抑制.
- 铁灭抑制剂和调节Stat1/Nrf2通路的策略显示,它有望预防Crizotinib诱导的肝损伤.
- MgIG和GA代表了潜在的治疗药物,可以提高Crizotinib在癌症治疗中的安全性.
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