2. Academic Validation
  3. Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice

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

  • Cell Death Discov. 2022 Sep 7;8(1):380. doi: 10.1038/s41420-022-01173-4.
Tianming Zhao  # 1 2,  Zihan Yu  # 1 3,  Lei Zhou  # 4,  Xiaoyu Wang 1 3,  Yangyang Hui 1 3,  Lihong Mao 1 3,  Xiaofei Fan 1 3,  Bangmao Wang 5 6,  Xingliang Zhao 7 8,  Chao Sun 9 10 11
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.
  • 2 Department of Gastroenterology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Zhongshan Road 321,Gulou District, 210008, Nanjing, Jiangsu, China.
  • 3 Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.
  • 4 Tianjin Neurological Institute, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.
  • 5 Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. [email protected].
  • 6 Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. [email protected].
  • 7 Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. [email protected].
  • 8 Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. [email protected].
  • 9 Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. [email protected].
  • 10 Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. [email protected].
  • 11 Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, 300308, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 36071041 DOI: 10.1038/s41420-022-01173-4
Abstract

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 (CCl4)-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 CCl4-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, CCl4 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 CCl4-induced ALI in mice.

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