Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-associated Steatohepatitis Development

Area of Science:

• Hepatology
• Molecular Biology
• Fibrosis Research

Background:

• Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) regulates the extracellular matrix and exhibits anti-fibrotic properties.
• The role and expression of RECK in metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis remain largely uncharacterized.

Purpose of the Study:

• To investigate the role of RECK in the pathogenesis of MASH and diet-induced liver fibrosis.
• To explore the therapeutic potential of RECK in MASH.

Main Methods:

• Generated a transgenic mouse model with hepatocyte-specific RECK overexpression.
• Utilized Western diet (WD) to induce MASH in wild-type and transgenic mice.
• Performed proteomic analysis and in vitro mechanistic studies.

Main Results:

• RECK expression was significantly decreased in human MASH liver biopsies and negatively correlated with disease severity.
• Hepatocyte-specific RECK overexpression ameliorated liver pathology in WD-induced MASH.
• RECK induction reduced ADAM10/17 activity, amphiregulin release, and hepatic stellate cell activation.

Conclusions:

• RECK acts as a novel upstream regulator of hepatic inflammation and fibrosis.
• RECK induction demonstrates hepatoprotective effects in MASH.
• RECK represents a promising therapeutic target for MASH.