UBQLN1 Inhibition reduces MASH progression through downregulating SIKE/p38 MAPK pathway in hepatocyte

Area of Science:

• Hepatology
• Molecular Biology
• Metabolic Diseases

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a growing cause of liver cirrhosis and cancer.
• The molecular mechanisms driving lipid dysregulation in MASH are not fully understood.

Purpose of the Study:

• To investigate the role of UBQLN1 in regulating hepatocyte lipid accumulation in MASH.
• To evaluate UBQLN1-targeted interventions as a potential therapy for MASH.

Main Methods:

• Analysis of clinical samples and cellular/animal MASH models.
• Utilized transcriptomics and LC-MS/MS to study UBQLN1's mechanism.
• Developed and tested red blood cell-derived extracellular vesicles (RBC-EVs) loaded with UBQLN1 siRNA (RBC-EVs@siUBQLN1).

Main Results:

• UBQLN1 was upregulated in MASH patients and mouse models, correlating with liver fat.
• UBQLN1 knockdown reduced steatosis, inflammation, and fibrosis in MASH mice.
• UBQLN1 promotes lipid accumulation via the UBQLN1-SIKE-p38 MAPK pathway.

Conclusions:

• The UBQLN1-SIKE-p38 MAPK pathway is crucial in MASH pathogenesis.
• RBC-EVs@siUBQLN1 effectively reduced liver fat and improved MASH progression in vivo.
• This study establishes a novel therapeutic strategy for MASH targeting UBQLN1.