TRIM29-dependent AKR1B10 degradation ameliorates MASH

Area of Science:

• Hepatology and Molecular Medicine
• Biochemistry and Molecular Biology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent liver disease with limited therapeutic options.
• Identifying novel molecular targets is crucial for developing effective MASH treatments.

Purpose of the Study:

• To identify novel molecular targets and therapeutic agents for MASH.
• To investigate the role of aldo-keto reductase family 1 member B10 (AKR1B10) in MASH pathogenesis.

Main Methods:

• Expression analysis of AKR1B10 in MASH patient tissues and serum.
• Genetic ablation of AKR1B10 in mouse models of diet-induced MASH.
• Investigating the interaction between tripartite motif protein 29 (TRIM29) and AKR1B10.
• Evaluating the therapeutic efficacy of coptisine (COP) in MASH mouse models.

Main Results:

• AKR1B10 is identified as a hallmark of MASH with elevated expression correlating with disease severity.
• Genetic deletion of AKR1B10 ameliorated MASH progression in mice.
• TRIM29 acts as an E3 ubiquitin ligase targeting AKR1B10 for degradation, mitigating MASH.
• Coptisine enhanced TRIM29-AKR1B10 interaction, accelerating AKR1B10 degradation and improving MASH outcomes.

Conclusions:

• The TRIM29/AKR1B10 axis represents a druggable target for MASH therapy.
• Coptisine demonstrates potential as a therapeutic candidate for MASH.