The Role of PAR2 in MASLD Progression and HCC Development

Area of Science:

• Hepatology
• Molecular Biology
• Pharmacology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is the primary cause of chronic liver disease, potentially progressing to hepatocellular carcinoma (HCC).
• Protease-activated receptor 2 (PAR2), a G-protein-coupled receptor, is upregulated in MASLD and liver fibrosis.
• PAR2 activation contributes to metabolic dysfunction via SREBP1c activation, AMPK inhibition, and insulin resistance.

Purpose of the Study:

• To review the current understanding of PAR2's role in MASLD pathogenesis.
• To explore the therapeutic potential of PAR2 as a target for MASLD and associated liver conditions.

Main Methods:

• Literature review of studies investigating PAR2 expression and function in liver disease models.
• Analysis of research on PAR2 inhibition in preclinical MASLD models.
• Examination of PAR2's involvement in inflammation, fibrosis, and HCC development.

Main Results:

• PAR2 inhibition effectively reduces MASLD progression in animal models.
• PAR2 blockade mitigates inflammation and fibrosis in advanced liver disease by inhibiting hepatic stellate cell activation and key mediators.
• PAR2 promotes HCC development by enhancing tumor proliferation, angiogenesis, and immune checkpoint inhibitor expression.

Conclusions:

• PAR2 is a significant contributor to MASLD pathogenesis and progression to HCC.
• Targeting PAR2 represents a promising therapeutic strategy for managing MASLD and preventing liver cancer.