Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation

Area of Science:

• Biochemistry
• Cell Biology
• Hepatology

Background:

• Tissue fibrosis results from extracellular matrix (ECM) imbalance.
• Current fibrosis treatments focus on reducing ECM production, not degradation.
• Hepatic stellate cells (HSCs) play a key role in ECM regulation.

Purpose of the Study:

• To investigate the role of acid ceramidase (aCDase) and ceramide in ECM degradation.
• To identify signaling pathways involved in ECM breakdown in HSCs.
• To explore aCDase as a therapeutic target for liver fibrosis.

Main Methods:

• Investigated signaling pathways in primary human HSCs.
• Utilized genetic reduction and pharmacological inhibition of aCDase.
• Employed carbon tetrachloride (CCl4) and FPC mouse models of liver fibrosis.
• Analyzed ceramide signaling in patients with metabolic dysfunction-associated steatotic liver disease.

Main Results:

• Inhibition of aCDase increased ceramide levels in HSCs.
• PKCα activation and ERK1/2 signaling induced MMP-1, promoting ECM degradation.
• Reduced aCDase activity led to collagen degradation and fibrosis resolution in mouse models.
• Ceramide signaling correlated with ECM remodeling in human liver disease patients.

Conclusions:

• Ceramide signaling is a key regulator of ECM degradation.
• aCDase inhibition promotes ECM breakdown and fibrosis resolution.
• aCDase is a potential therapeutic target for reversing liver fibrosis.