# The Role of PAR2 in MASLD Progression and HCC Development

## TL;DR

This paper reviews how PAR2 contributes to liver disease progression and cancer, highlighting its potential as a therapeutic target.

## Contribution

The paper synthesizes recent findings on PAR2's role in MASLD and HCC, emphasizing its therapeutic potential.

## Key findings

- PAR2 activation is linked to metabolic dysfunction and insulin resistance in MASLD.
- Inhibiting PAR2 reduces liver fibrosis and inflammation in animal models.
- PAR2 promotes cancer progression by enhancing tumor growth and immune evasion.

## Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently become the leading cause of chronic liver disease and can progress to hepatocellular carcinoma (HCC) through multiple pathogenic mechanisms. Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor activated by proteases such as trypsin, tryptase or coagulation factors VII and Xa. Recent studies have shown that PAR2 expression is increased in the liver of patients with MASLD or liver fibrosis. Its activation is linked to metabolic dysfunction through several pathways, including SREBP1c activation, AMPK inhibition and Akt-induced insulin resistance. Inhibition of PAR2 has been effective in reducing MASLD progression in different animal models. Notably, PAR2 blockade has also been effective in more advanced stages of the disease by dampening chronic inflammation and fibrogenesis through the inhibition of hepatic stellate cell activation and of TGF-β and SerpinB3 production. PAR2 also plays a role in cancer development, promoting tumour proliferation, angiogenesis and expression of immune checkpoint inhibitors (like PD-L1, CD47 and CD24). Due to its multifaceted involvement in liver disease, PAR2 is emerging as a key therapeutic target in this clinical context. This review aims to summarise current knowledge on PAR2′s role in MASLD and its potential as a therapeutic target.