Related Experiment Video
Updated: Mar 7, 2026
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman
Pi-Xiao Wang1,2,3,4, Yan-Xiao Ji2,3,4, Xiao-Jing Zhang1,2,3,4
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Abstract:
Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.
Insights
CASP8 and FADD-like apoptosis regulator (CFLAR) suppresses nonalcoholic steatohepatitis (NASH) by blocking ASK1 signaling. A CFLAR-derived peptide shows therapeutic potential for NASH and metabolic disorders.
Area of Science:
- Hepatology
- Molecular Biology
- Drug Discovery
Background:
- Nonalcoholic steatohepatitis (NASH) is a progressive liver disease linked to metabolic syndrome, with no current effective pharmacological treatments.
- NASH carries a high risk of severe liver damage, necessitating novel therapeutic strategies.
Purpose of the Study:
- To identify key molecular suppressors of steatohepatitis and associated metabolic disorders.
- To investigate the role of CASP8 and FADD-like apoptosis regulator (CFLAR) in NASH pathogenesis.
- To explore therapeutic strategies targeting CFLAR-mediated pathways.
Main Methods:
- Mechanistic studies to elucidate CFLAR's interaction with MAP3K5 (ASK1) and its downstream signaling.
- In vivo studies using mouse and monkey models to assess the therapeutic efficacy of a CFLAR-derived peptide delivered via adeno-associated virus 8 vectors.
- Biochemical assays to analyze ASK1 N-terminus-mediated dimerization inhibition.
Main Results:
- CFLAR acts as a crucial suppressor of steatohepatitis and metabolic disorders.
- CFLAR directly targets MAP3K5 (ASK1), inhibiting its N-terminus-mediated dimerization and blocking ASK1/JNK1 signaling.
- A small peptide segment of CFLAR, delivered via AAV8, effectively attenuated NASH and metabolic disorder progression in preclinical models.
Conclusions:
- CFLAR is a key suppressor of nonalcoholic steatohepatitis and its metabolic complications.
- Targeting ASK1 dimerization presents a novel therapeutic avenue for NASH.
- CFLAR-peptide mimicking drugs and small-molecule inhibitors of ASK1 dimerization offer promising strategies for NASH treatment.
More Related Videos
07:03Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss
Published on: July 19, 2024
04:14Incorporation of a Survivable Liver Biopsy Procedure in Mice to Assess Non-alcoholic Steatohepatitis NASH Resolution
Published on: April 16, 2019
