A non-apoptotic caspase-8-meteorin pathway in hepatocytes promotes MASH fibrosis

Area of Science:

• Hepatology
• Molecular Biology
• Fibrosis Research

Background:

• Metabolic-dysfunction-associated steatohepatitis (MASH) is a primary driver of chronic liver disease.
• Limited understanding of MASH-induced liver fibrosis hinders effective therapeutic strategies.

Purpose of the Study:

• To elucidate the role of hepatocyte caspase-8 in MASH-induced liver fibrosis.
• To identify novel molecular pathways and potential therapeutic targets for MASH fibrosis.

Main Methods:

• Analysis of caspase-8 expression in human and experimental MASH.
• Hepatocyte-specific caspase-8 deletion in MASH mouse models.
• Investigation of the caspase-8-YY1-meteorin-c-Kit-STAT3 signaling axis.
• Assessment of meteorin's role in hepatic stellate cell activation and fibrosis.

Main Results:

• Hepatocyte caspase-8 drives MASH fibrosis through an apoptosis-independent mechanism.
• Caspase-8 deletion in hepatocytes suppresses liver fibrosis and hepatic stellate cell activation in MASH.
• A novel pathway involving hepatocyte caspase-8, YY1, and meteorin activates hepatic stellate cells.
• Meteorin acts as a secretory activator of hepatic stellate cells via the c-Kit-STAT3 pathway.

Conclusions:

• Hepatocyte caspase-8 plays a critical, non-apoptotic role in promoting MASH fibrosis.
• Meteorin is a newly identified activator of hepatic stellate cells, crucial in MASH pathogenesis.
• The identified caspase-8-meteorin pathway represents a promising therapeutic target for MASH-associated liver fibrosis.