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

Summary

This study identifies a non-apoptotic hepatocyte caspase‑8–YY1–meteorin axis that activates hepatic stellate cells via c‑Kit–STAT3 to promote MASH fibrosis. Deleting hepatocyte caspase‑8 reduced fibrosis without altering apoptosis; meteorin restoration rescued fibrosis, while meteorin silencing lowered fibrosis. Meteorin was elevated in human and mouse MASH, highlighting a targetable pathway.

Key Findings

• Hepatic caspase‑8 expression correlates with fibrosis in human and experimental MASH.
• Hepatocyte-specific caspase‑8 deletion suppresses fibrosis and HSC activation without affecting hepatocyte apoptosis.
• A caspase‑8–YY1 pathway induces secreted meteorin, which activates HSCs via c‑Kit–STAT3.
• Meteorin is elevated in human and mouse MASH; restoring hepatocyte meteorin rescues fibrosis, silencing reduces fibrosis.

Clinical Implications

Suggests biomarker and therapeutic targeting of hepatocyte caspase‑8/YY1 or secreted meteorin, or downstream c‑Kit–STAT3, to prevent or reverse MASH fibrosis; supports patient stratification by meteorin levels.

Limitations

• Studies predominantly in male mice; sex differences and human causal validation remain to be established.
• No pharmacologic caspase‑8/meteorin pathway inhibitor tested in vivo in this report.

Future Directions

Develop and test inhibitors/antagonists of meteorin or c‑Kit–STAT3, and evaluate meteorin as a biomarker for stratified anti-fibrotic trials in MASH.