Zhang Xuliang, Du Jiayu, Huo Siming, Li Bo, Zhang Jian, Song Miao, Shao Bing, Li Yanfei
Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China.
Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China.
Food Chem Toxicol. 2023 Apr;174:113706. doi: 10.1016/j.fct.2023.113706. Epub 2023 Mar 5.
Hexafluoropropylene oxide trimer acid (HFPO-TA) causes hepatotoxicity, however, its underlying mechanisms have not been conclusively determined. We investigated the effects of HFPO-TA on mice liver after 28 days of orally administered 0 or 0.5 mg/kg/d HFPO-TA. Administration of HFPO-TA induced mitochondrial ROS (mtROS) overexpression, cGAS-STING signaling activation, pyroptosis and fibrosis in mice liver. To determine the HFPO-TA-associated hepatotoxic mechanisms, mtROS, cGAS-STING signaling and pyroptosis intervention assays were performed in HFPO-TA-exposed mice liver. First, mtROS was found to be an upstream regulatory target of cGAS-STING signaling, pyroptosis and fibrosis. Second, cGAS-STING signaling was established to be an upstream regulatory mechanism of pyroptosis and fibrosis. Finally, pyroptosis was shown to regulate fibrosis. The above results confirm that HFPO-TA causes mice liver fibrosis via mtROS/cGAS-STING/NLRP3-mediated pyroptosis.
六氟环氧丙烷三聚体酸（HFPO-TA）会导致肝毒性，然而，其潜在机制尚未最终确定。我们研究了在口服给予0或0.5毫克/千克/天的HFPO-TA 28天后，HFPO-TA对小鼠肝脏的影响。给予HFPO-TA可诱导小鼠肝脏线粒体活性氧（mtROS）过表达、cGAS-STING信号激活、细胞焦亡和纤维化。为了确定与HFPO-TA相关的肝毒性机制，在暴露于HFPO-TA的小鼠肝脏中进行了mtROS、cGAS-STING信号和细胞焦亡干预试验。首先，发现mtROS是cGAS-STING信号、细胞焦亡和纤维化的上游调节靶点。其次，确定cGAS-STING信号是细胞焦亡和纤维化的上游调节机制。最后，显示细胞焦亡可调节纤维化。上述结果证实，HFPO-TA通过mtROS/cGAS-STING/NLRP3介导的细胞焦亡导致小鼠肝脏纤维化。
