Liver Endothelia Orchestrate MASH‐Associated Macrophage Zonation Through FSTL1‐ITGA4 Axis
Lin Sun, Zhensheng Yue, Zhiqiang Fang, Hao Xu, Wei Du, Yuwei Ling, Jingjing Liu, Ping Song, Fei He, Juanli Duan, Lin WangABSTRACT
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.