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

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.

The Role of Gasdermin-D-Mediated Pyroptosis in Organ Injury and Its Therapeutic Implications

“…Other studies investigated the effect of inhibiting hepatocyte pyroptosis in severe forms of liver injury. Wang et al 20 show that phenethyl isothiocyanate (PEITC), a natural product found in cruciferous vegetables, can significantly reduce both chemical and inflammatory liver injury. Similar to JZLGD, PEITC targets NLRP3 and Caspase-1.…”

“…Additionally, PEITC directly inhibits GSDMD cleavage and membrane pore formation by binding to cysteine 191 on GSDMD. 20 …”

The Role of the NLRP3 Inflammasome and Programmed Cell Death in Acute Liver Injury

“…Phenethyl isothiocyanate (PEITC) is a widely distributed natural compound derived from the secondary metabolites of Brassicaceae plants; it has antimicrobial, anti-inflammatory, and antioxidant properties [ 170 , 171 ]. Wang et al, by constructing a Con A-induced acute immune liver injury model in mice, found that PEITC could reduce NLRP3 production and casp1 and GSDMD cleavage in the liver of ALI-suffering mice and directly interact with the cysteine at position 191 of GSDMD to inhibit hepatocyte pyroptosis, thereby exerting a significant hepatoprotective effect [ 172 ]. The work of Shi et al showed that dimethyl fumarate promoted NLRP3 phosphorylation on Ser/Thr residues at specific sites of protein kinase A (PKA) and enhanced PKA signaling to inhibit NLRP3 inflammasome activation, pyroptosis, and IL-1 β Secretion, thereby treating Con A-induced AIH [ 173 ].…”

Inflammasome and pyroptosis in autoimmune liver diseases

“…It has been revealed that the N-terminal domain of GSDMD is responsible for some of the negative consequences observed in metabolic liver illnesses, such as NAFLD. Some studies have found that inhibition of GSDMD protects mice from this type of liver disease ( 96 ). In contrast, GSDMD deficiency was found to cause more portal vein and lobular inflammation, a wider hepatic conjunctival necrotic area, higher serum transaminase levels, and more extensive hepatocyte apoptosis after ConA induction ( 86 ).…”