Liver Endothelia Orchestrate MASH-Associated Macrophage Zonation Through FSTL1-ITGA4 Axis
Lin Sun1, Zhensheng Yue1,2, Zhiqiang Fang1
1Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Background And Aims:
Liver zonation is fundamental to hepatic physiology. The zonal loss of Kit in liver sinusoidal endothelial cells (LSECs) during MASH suggests a role in niche maintenance, but its regulatory function is unclear. This study aimed to define how the zonated LSEC Kit controls macrophage distribution in MASH.
Methods:
We used zonal LSEC isolation, endothelial-specific knockout mice, spatial transcriptomics, and human data to dissect this axis.
Results:
Pericentral LSEC Kit maintains homeostasis by suppressing FSTL1 via STAT2 phosphorylation. In MASH, Kit loss triggers centrilobular FSTL1 upregulation. The resulting FSTL1 gradient drives centrilobular accumulation of pro-inflammatory ITGA4+ macrophages via NF-κB. Inhibiting FSTL1 or ITGA4 restored macrophage zonation and ameliorated MASH.
Conclusion:
The Kit/STAT2/FSTL1/ITGA4 axis is a master regulator of inflammatory zonation in MASH, revealing how zonal endothelial dysfunction drives spatial immune reorganization and offering a new framework for therapy.
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