Selonsertib, a potential drug for liver failure therapy by rescuing the mitochondrial dysfunction of macrophage via
Guohua Lou1, Aichun Li1, Yelei Cen1
1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, 6A-17, Hangzhou, 310003, China.
Background:
Acute liver failure (ALF) is associated with a high mortality rate, and there are still no effective treatments except liver transplantation and artificial liver therapies. This study aimed to determine the effects, therapeutic window and mechanisms of selonsertib, a selective inhibitor of ASK1, for ALF therapy.
Results:
Lipopolysaccharide and D-galactosamine (LPS/GalN) were used to simulate ALF. We found that selonsertib pretreatment significantly ameliorated ALF, as determined by reduced hepatic necrosis and serum alanine aminotransferase, aspartate aminotransferase and inflammatory cytokine levels. However, selonsertib is only effective early after LPS/GalN administration, and the limited therapeutic window is related to the activation and mitochondrial translocation of JNK and DRP1. Further experiments revealed that selonsertib could alleviate LPS-induced mitochondrial damage in macrophages by evaluating the mitochondrial membrane potential and mitochondrial permeability transition pore opening in macrophages. Selonsertib also suppressed the release of inflammatory cytokines from macrophages by reducing DRP1-mediated mitochondrial dysfunction, which was confirmed by using mdivi, a specific DRP1 inhibitor.
Conclusions:
Selonsertib protected against LPS/GalN-induced ALF by attenuating JNK-mediated DRP1 mitochondrial translocation and then rescuing mitochondrial damage in macrophages and may have therapeutic potential for early ALF patients.
Insights
Selonsertib, a drug for acute liver failure (ALF), shows promise when given early. It protects liver cells by improving mitochondrial function and reducing inflammation, but its effectiveness window is limited.
Area of Science:
- Hepatology
- Pharmacology
- Cell Biology
Background:
- Acute liver failure (ALF) presents a high mortality risk with limited treatment options.
- Liver transplantation and artificial liver support are current mainstays for ALF.
- Investigating novel therapeutic agents for ALF is critical.
Purpose of the Study:
- To evaluate the therapeutic effects of selonsertib, a selective ASK1 inhibitor, in ALF.
- To determine the therapeutic window for selonsertib intervention in ALF.
- To elucidate the underlying mechanisms of selonsertib's action in ALF.
Main Methods:
- Acute liver failure (ALF) was induced using lipopolysaccharide and D-galactosamine (LPS/GalN) in a preclinical model.
- Selonsertib's efficacy was assessed by measuring liver damage markers and inflammatory cytokines.
- Mechanisms involving JNK, DRP1, and mitochondrial function in macrophages were investigated.
Main Results:
- Selonsertib pretreatment significantly reduced hepatic necrosis and serum liver enzymes in an ALF model.
- Therapeutic benefit of selonsertib was observed only within a limited early window post-LPS/GalN administration.
- Selonsertib alleviated LPS-induced mitochondrial damage and inflammatory cytokine release from macrophages by inhibiting DRP1 translocation.
Conclusions:
- Selonsertib demonstrates protective effects against LPS/GalN-induced ALF.
- The mechanism involves attenuation of JNK-mediated DRP1 mitochondrial translocation, preserving macrophage mitochondrial function.
- Selonsertib may hold therapeutic potential for patients in the early stages of ALF.
More Related Videos
08:39Experimental Protocol for Detecting Mitochondrial Function in Hepatocytes Exposed to Organochlorine Pesticides
Published on: September 16, 2020
07:15Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
01:24Liver Regeneration
Cells of Liver
The liver comprises four major types of cells— hepatocytes, stellate, Kupffer, and sinusoidal endothelial cells. The hepatocytes are...