Liver Endothelia Orchestrate MASH-Associated Macrophage Zonation Through FSTL1-ITGA4 Axis

Area of Science:

• Hepatology
• Immunology
• Endothelial Cell Biology

Background:

• Liver zonation is crucial for liver function.
• Loss of Kit in liver sinusoidal endothelial cells (LSECs) during MASH is linked to niche maintenance, but its role is unclear.
• Understanding LSEC Kit's regulation of macrophage distribution in MASH is essential.

Purpose of the Study:

• To define how zonated LSEC Kit controls macrophage distribution in MASH.
• To elucidate the molecular mechanisms underlying LSEC Kit's function in MASH.
• To identify potential therapeutic targets for MASH based on LSEC-macrophage interactions.

Main Methods:

• Zonal LSEC isolation
• Endothelial-specific knockout mouse models
• Spatial transcriptomics
• Analysis of human MASH data

Main Results:

• Pericentral LSEC Kit suppresses FSTL1 via STAT2 phosphorylation, maintaining homeostasis.
• Kit loss in MASH leads to centrilobular FSTL1 upregulation.
• FSTL1 gradient drives centrilobular accumulation of pro-inflammatory ITGA4+ macrophages via NF-κB.
• Inhibition of FSTL1 or ITGA4 restored macrophage zonation and ameliorated MASH.

Conclusions:

• The Kit/STAT2/FSTL1/ITGA4 axis is a key regulator of inflammatory zonation in MASH.
• Zonal endothelial dysfunction drives spatial immune reorganization in MASH.
• This axis provides a novel therapeutic framework for MASH treatment.