Metabolic stress–activated endothelial STING rewires the sinusoidal immune niche to promote MASLD progression
Zhi-Bin Lin, Peng Zou, Xian-Yi Ma, Jun-Bo Song, Hong Zhang, Wei Du, Dan Wei, Ping Song, Xin Hong, Jing-Jing Liu, Zhi-Qiang Fang, Hao Xu, Fei He, Juan-Li Duan, Ke-Feng Dou, Lin Wang
Zhi-Bin Lin, Peng Zou, Xian-Yi Ma, Jun-Bo Song, Hong Zhang, Wei Du, Dan Wei, Ping Song, Xin Hong, Jing-Jing Liu, Zhi-Qiang Fang, Hao Xu, Fei He, Juan-Li Duan, Ke-Feng Dou, Lin Wang
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Research Article Hepatology Metabolism

Metabolic stress–activated endothelial STING rewires the sinusoidal immune niche to promote MASLD progression

Abstract

Liver sinusoidal endothelial cells (LSECs) regulate nutrient flux and immune surveillance within the hepatic niche, yet how they function as metabolic stress sensors that instruct adaptive immune remodeling during metabolic dysfunction–associated steatotic liver disease (MASLD) remains unclear. Here, single-nucleus transcriptomics of human MASLD revealed stage-dependent activation of cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling in LSEC comparable with that in macrophages, with endothelial activation showing greater responsiveness to metabolic stress. Endothelium-specific STING deletion attenuated steatohepatitis and fibrosis in mice. Mechanistically, LSEC-intrinsic STING activation reprogrammed the angiocrine landscape through NF-κB–mediated transcriptional repression of the endothelium-derived factor BMP4. Loss of BMP4 disrupted the tolerance-supporting sinusoidal immunometabolic niche, skewing CD4+ T cell differentiation toward pathogenic Th17 states while destabilizing Treg, collectively exacerbating hepatic metabolic failure. In human MASLD, endothelial STING activity inversely correlated with BMP4 expression at single-cell resolution. Targeted delivery of a STING inhibitor to LSECs using peptide-functionalized nanoparticles restored hepatic immunometabolic balance at one-tenth the systemic dose. Together, these findings establish endothelial STING as a metabolically responsive vascular immune checkpoint that links chronic metabolic stress to adaptive immune remodeling and fibrotic progression.

Authors

Zhi-Bin Lin, Peng Zou, Xian-Yi Ma, Jun-Bo Song, Hong Zhang, Wei Du, Dan Wei, Ping Song, Xin Hong, Jing-Jing Liu, Zhi-Qiang Fang, Hao Xu, Fei He, Juan-Li Duan, Ke-Feng Dou, Lin Wang

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Figure 7

Human single-cell analysis validates a conserved endothelial STING-BMP4 angiocrine checkpoint.

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Human single-cell analysis validates a conserved endothelial STING-BMP4 ...
(A) UMAP visualization of all cell clusters from human liver scRNA-seq data (GEO: GSE136103). (B) UMAP plot showing STING expression across all cell types. (C) Dot plot showing the expression of STING, IRF3, and TBK1 across all cell types. (D) Evaluation of cGAS/STING signaling pathway activation across all cell types using 4 functional scores and their average. (E) Average cGAS/STING pathway activation scores in various cell types from healthy and MASLD livers. (F) UMAP plot showing STING expression specifically in endothelial cells. (G) GSEA of TGF-β and BMP signaling pathway activation in STING– versus STING+ endothelial cells. (H) UMAP plot showing BMP4 expression across all cell types. (I and J) Dot plots showing the expression of BMP2, BMP4, and BMP6 in all cell types (I) and specifically in endothelial cells (J). (K) UMAP visualization of CD4+ T cell clusters. (L and M) CellChat analysis showing BMP signaling interactions between STING– or STING+ endothelial cells and CD4+ T cells (L) along with the overall interaction score (M). ***P < 0.001. (E) Wilcoxon test. (G) Permutation test.