Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
Liver Endothelia Orchestrate MASH-Associated Macrophage Zonation Through FSTL1-ITGA4 Axis.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Sun Lin, Yue Zhensheng, Fang Zhiqiang, Xu Hao, Du Wei, Ling Yuwei, Liu Jingjing, Song Ping, He Fei, Duan Juanli, Wang Lin
Аннотация
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.
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.