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

Jie Wang,Qiang Xu,Jingcai Cheng,Xuefeng Wu,Ke Shi,Shuaifei Li,Xudong Wu,Mei Bai,Ning An,Yan Shen,Ronghui Du

doi:10.3389/fimmu.2022.825428

Abstract

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 (CCl4)-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). In vitro 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 via direct inhibition of GSDMD, which may provide a new potential therapeutic strategy for ALI.

Highlights

Acute liver injury (ALI) is one of the most common clinical liver diseases and is often caused by viruses, alcohol, drugs, etc
We found that the liver index of mice in the concanavalin A (ConA)-treated group was significantly higher than that in the normal group, while the liver index of mice treated with phenethyl isothiocyanate (PEITC) decreased in a dose-dependent manner (Figure 1D)
The spleen index of mice in the ConA-treated group was significantly increased in comparison with that of the normal group, while the spleen index of mice from the PEITC and PEITC groups decreased in a dose-dependent manner, indicating that PEITC

Summary

Introduction

Acute liver injury (ALI) is one of the most common clinical liver diseases and is often caused by viruses, alcohol, drugs, etc. If it is not treated in time, it can develop into acute liver failure, chronic liver injury, or hepatocellular carcinoma, which seriously threatens human quality of life and health. In mouse sepsis models induced by lipopolysaccharide (LPS), the level of pyroptosis is positively correlated with the severity of liver injury [5]. Signaling pathways involved in pyroptosis in hepatocytes and nonparenchymal cells were significantly enhanced in concanavalin A (ConA)-induced mouse ALI models [6]

Methods

Results

Conclusion