Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice

• Published in: Cell death discovery 2022-09, Vol.8 (1), p.380-380, Article 380
• Main Authors: Zhao, Tianming, Yu, Zihan, Zhou, Lei, Wang, Xiaoyu, Hui, Yangyang, Mao, Lihong, Fan, Xiaofei, Wang, Bangmao, Zhao, Xingliang, Sun, Chao
• Format: Article
• Language: English
• Subjects: 631/154/436; 631/80/82; 692/699/1503/1607/2749; Apoptosis; Biochemistry; Biomedical and Life Sciences; Carbon tetrachloride; Cell Biology; Cell Cycle Analysis; Ferroptosis; Glutathione peroxidase; Hepatocytes; Life Sciences; Lipid peroxidation; Lipids; Liver; Mitochondria; Physical characteristics; Protein adducts; Reactive oxygen species; siRNA; Stem Cells
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-022-01173-4

Hepatocellular death is a sensitive parameter for detecting acute liver injury (ALI) of toxic, viral, metabolic, and autoimmune origin. Ferroptosis has recently been implicated in carbon tetrachloride (CCl 4 )-induced ALI. However, the underpinning mechanism and mechanistic basis remain elusive. In this study, bicyclol, a proprietary hepatoprotectant in China, and ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) were administered in CCl 4 -injured mice. A panel of ferroptosis-related markers, including mitochondria morphology, reactive oxygen species production, protein adducts in response to lipid peroxidation, and key modulators of ferroptotic process, was determined in vivo. Erastin-treated L-O2 hepatocytes were transfected with glutathione peroxidase 4 (GPx4) or nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA to delineate the pathway of bicyclol against ferroptosis in vitro. As a result, CCl 4 led to iron accumulation, excessive reactive oxygen species production, enhanced lipid peroxidation, and characteristic morphological changes in mitochondria, along with a decrease in GPx4 and xCT protein levels in ALI mice liver, all of which were generally observed in ferroptosis. The use of Fer-1 further corroborated that ferroptosis is responsible for liver damage. Bicyclol exerted its hepatoprotection by preventing the aforesaid ferroptotic process. Furthermore, bicyclol alleviated erastin-induced cellular inviability, destruction, and lipid peroxidation in vitro. Knockdown of GPx4 diminished these protective activities against perturbations associated with ferroptosis in L-O2 hepatocytes. Additionally, Nrf2 silencing drastically reduced GPx4 levels, and further impeded the medicinal effects of bicyclol. In summary, positively regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in CCl 4 -induced ALI in mice.