Endothelial RUNX3 controls LSEC dysfunction and angiocrine LRG1 signaling to prevent liver fibrosis

Area of Science:

• Hepatology and Vascular Biology
• Molecular Mechanisms of Fibrosis
• Cellular Signaling in Liver Disease

Background:

• Liver fibrosis is a significant global health issue with limited treatment options.
• Liver sinusoidal endothelial cells (LSECs) are critical for liver homeostasis and disease.
• The role of RUNX3 in LSECs during liver fibrosis was previously unknown.

Purpose of the Study:

• To investigate the role of RUNX3 in regulating LSEC gatekeeping functions.
• To identify novel angiocrine regulators involved in liver fibrosis.
• To elucidate the mechanisms by which RUNX3 deficiency impacts LSEC function and liver fibrosis.

Main Methods:

• Endothelial-specific Runx3 deficiency mouse models were utilized.
• Mechanistic studies involved human immortalized and mouse primary LSECs.
• Single-cell RNA sequencing and quantitative RT-PCR identified key molecular players.
• In vitro and coculture experiments assessed LRG1 secretion and function.
• Circulating LRG1 levels were measured in mouse models and human patients.

Main Results:

• Endothelial Runx3 deficiency led to spontaneous liver fibrosis and LSEC dysfunction.
• IL-6/JAK/STAT3 pathway activation was linked to LSEC dysfunction without RUNX3.
• Leucine-rich alpha-2-glycoprotein 1 (LRG1) was upregulated in RUNX3-deficient LSECs.
• Secreted LRG1 activated hepatic stellate cells (HSCs) via TGFBR1-SMAD2/3 signaling.
• Elevated circulating LRG1 levels were observed in liver fibrosis models and patients.

Conclusions:

• Endothelial RUNX3 is essential for maintaining LSEC gatekeeping functions.
• RUNX3 deficiency promotes liver fibrosis through LSEC dysfunction and LRG1 secretion.
• Profibrotic angiocrine LRG1 represents a potential therapeutic target for liver fibrosis.