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

ABSTRACT 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.