Direct Inhibition of GSDMD by PEITC Reduces Hepatocyte Pyroptosis and Alleviates Acute Liver Injury in Mice

Acute liver injury (ALI), often caused by viruses, alcohol, drugs, etc., is one of the most common clinical liver diseases. Although pyroptosis plays an important role in ALI, there is still a lack of effective clinical drugs related to this mechanism. Here, we show that phenethyl isothiocyanate (PE...

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Bibliographic Details
Published in:Frontiers in immunology 2022-01, Vol.13, p.825428-825428
Main Authors: Wang, Jie, Shi, Ke, An, Ning, Li, Shuaifei, Bai, Mei, Wu, Xudong, Shen, Yan, Du, Ronghui, Cheng, Jingcai, Wu, Xuefeng, Xu, Qiang
Format: Article
Language:English
Subjects:
acute liver injury
Animals
Caspase 1 - metabolism
Chemical and Drug Induced Liver Injury - metabolism
gasdermin D
hepatocyte
Hepatocytes - metabolism
Immunology
Isothiocyanates - pharmacology
Liver - metabolism
Male
Mice
Mice, Inbred ICR
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
PEITC
Phosphate-Binding Proteins - metabolism
Pore Forming Cytotoxic Proteins - metabolism
Pyroptosis
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Summary:Acute liver injury (ALI), often caused by viruses, alcohol, drugs, etc., is one of the most common clinical liver diseases. Although pyroptosis plays an important role in ALI, there is still a lack of effective clinical drugs related to this mechanism. Here, we show that phenethyl isothiocyanate (PEITC), a natural compound present in cruciferous vegetables, can significantly alleviate concanavalin A (ConA)-induced inflammatory liver damage and carbon tetrachloride (CCl )-induced chemical liver damage in a dose-dependent manner. PEITC dose-dependently reversed the ALI-induced increase in plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and reduced the protein levels of hepatocyte pyroptosis markers such as Nod-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, and cleaved gasdermin D (GSDMD). experiments have also verified the inhibitory effect of PEITC on hepatocyte pyroptosis. Furthermore, PEITC inhibits pyroptosis by interacting with cysteine 191 of GSDMD. In summary, our findings establish a role for PEITC in rescuing hepatocyte pyroptosis direct inhibition of GSDMD, which may provide a new potential therapeutic strategy for ALI.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2022.825428