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VX-765 inhibits pyroptosis and reduces inflammation to prevent acute liver failure by upregulating PPARα expression
Mingjing Jiao1, Jiachao Wang2, Wenpeng Liu3
1Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
Introduction And Objectives:
As a fatal clinical syndrome, acute liver failure (ALF) is characterized by overwhelming liver inflammation and hepatic cell death. Finding new therapeutic methods has been a challenge in ALF research. VX-765 is a known pyroptosis inhibitor and has been reported to prevent damage in a variety of diseases by reducing inflammation. However, the role of VX-765 in ALF is still unclear.
Materials And Methods:
ALF model mice were treated with D-galactosamine (D-GalN) and lipopolysaccharide (LPS). LO2 cells were stimulated with LPS. Thirty subjects were enrolled in clinical experiments. The levels of inflammatory cytokines, pyroptosis-associated proteins and peroxisome proliferator-activated receptor α (PPARα) were detected using quantitative reverse transcription-polymerase chain reaction (qRT‒PCR), western blotting and immunohistochemistry. An automatic biochemical analyzer was used to determine the serum aminotransferase enzyme levels. Hematoxylin and eosin (HE) staining was used to observe the pathological features of the liver.
Results:
With the progression of ALF, the expression levels of interleukin (IL) -1β, IL-18, caspase-1, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased. VX-765 could reduce the mortality rate of ALF mice, relieve liver pathological damage, and reduce inflammatory responses to protect against ALF. Further experiments showed that VX-765 could protect against ALF through PPARα, and this protective effect against ALF was reduced in the context of PPARα inhibition.
Conclusions:
As ALF progresses, inflammatory responses and pyroptosis deteriorate gradually. VX-765 can inhibit pyroptosis and reduce inflammatory responses to protect against ALF by upregulating PPARα expression, thus providing a possible therapeutic strategy for ALF.
Insights
VX-765, a pyroptosis inhibitor, reduces mortality and liver damage in acute liver failure (ALF) by inhibiting inflammation and upregulating PPARα. This offers a potential new therapy for ALF.
Area of Science:
- Hepatology
- Immunology
- Pharmacology
Background:
- Acute liver failure (ALF) is a severe condition marked by extensive liver inflammation and cell death, posing therapeutic challenges.
- Pyroptosis, a pro-inflammatory form of cell death, and associated inflammatory cytokines are key contributors to ALF progression.
- VX-765, a known pyroptosis inhibitor, has shown potential in reducing inflammation in various diseases, but its role in ALF remains unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of VX-765 in a mouse model of acute liver failure.
- To elucidate the underlying mechanisms of VX-765's protective effects in ALF, focusing on pyroptosis and inflammatory pathways.
- To explore the role of peroxisome proliferator-activated receptor α (PPARα) in mediating VX-765's efficacy.
Main Methods:
- Acute liver failure was induced in mice using D-galactosamine (D-GalN) and lipopolysaccharide (LPS).
- LO2 cells were stimulated with LPS to mimic inflammatory conditions.
- Levels of inflammatory cytokines (IL-1β, IL-18), pyroptosis markers (caspase-1), PPARα, and liver enzymes (ALT, AST) were quantified using qRT-PCR, western blotting, and biochemical assays.
- Liver pathology was assessed via HE staining.
Main Results:
- ALF progression was associated with increased levels of IL-1β, IL-18, caspase-1, ALT, and AST.
- VX-765 treatment significantly reduced mortality, alleviated liver damage, and suppressed inflammatory responses in ALF mice.
- The protective effects of VX-765 against ALF were diminished upon PPARα inhibition, indicating its crucial role.
Conclusions:
- VX-765 demonstrates significant protective effects against acute liver failure by inhibiting pyroptosis and reducing inflammation.
- Upregulation of PPARα expression by VX-765 is a key mechanism underlying its therapeutic benefits in ALF.
- VX-765 represents a promising therapeutic strategy for managing acute liver failure.
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