2. Academic Validation
  3. Inhibition of TWEAK/Tnfrsf12a axis protects against acute liver failure by suppressing RIPK1-dependent apoptosis

Inhibition of TWEAK/Tnfrsf12a axis protects against acute liver failure by suppressing RIPK1-dependent apoptosis

  • Cell Death Discov. 2022 Jul 19;8(1):328. doi: 10.1038/s41420-022-01123-0.
Zhijie Li 1 2 3,  Heming Wang 4,  Junjin Zhu 1,  Ning Nan 1 2 3,  Yi Lin 1,  Xuran Zhuang 1,  Ling Li 1,  Yamin Zhang 5,  Pengyu Huang 6
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 4 Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 5 Tianjin First Central Hospital, Tianjin, 300190, China. 13802122219@163.com.
  • 6 Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China. huangpengyu@yeah.net.
PMID: 35853848 DOI: 10.1038/s41420-022-01123-0
Abstract

Acute liver failure (ALF) is a severe clinical syndrome characterized by massive death of hepatocytes in a short time, resulting in coagulopathy and hepatic encephalopathy, with a high mortality in patients without pre-existing liver disease. Effective treatment of ALF is currently limited to liver transplantation, highlighting the need for new target therapies. Here, we found that expression of hepatic tumor necrosis factor-like weak inducer of Apoptosis (TWEAK) and its receptor tumor necrosis factor receptor superfamily member 12A (Tnfrsf12a) were significantly increased during ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Inhibition of TWEAK/Tnfrsf12a axis markedly attenuated TAA or APAP-induced ALF. Moreover, our results demonstrated that TWEAK/Tnfrsf12a axis induced receptor-interacting protein kinase 1 (RIPK1)-dependent Apoptosis of hepatocytes, instead of Necroptosis or Pyroptosis. Notably, hepatic TNFRSF12A and TWEAK levels were also significantly increased in liver biopsies from ALF patients. In summary, our results demonstrate that during ALF, TWEAK/Tnfrsf12a axis activates RIPK1 in hepatocytes, leading to RIPK1-dependent Apoptosis and subsequent liver injury. Therefore, inhibition of either TWEAK/Tnfrsf12a axis or RIPK1-dependent Apoptosis attenuates liver injury, providing a new potential therapeutic target for the treatment of ALF.

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