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 8

Delivery of a STING inhibitor via LSEC-directed RLTR-liposome ameliorates MASH progression.

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Delivery of a STING inhibitor via LSEC-directed RLTR-liposome ameliorate...
(A) Schematic illustrating the construction of RLH nanoparticles. (B) Schematic of the therapeutic experiments using H-151 and RLH. (C and D) In vivo distribution of DiD perchlorate–labeled RLH in major organs monitored by fluorescence imaging (C) and immunofluorescence verification of RLH uptake by LSECs (D). Scale bar: 20 μm. (E) Western blot analysis of p65, phospho-p65 (p-p65), IRF3, and p-IRF3 in LSECs and KCs isolated from the WD-fed mice treated with RLH or empty liposome (CT). (F–I) H&E (F), Oil Red O (ORO; G), and Masson’s trichrome (H) staining of liver sections from the 4 groups, followed by NAS and SAF scoring (I; n = 5). Scale bar: 100 μm (G), 200 μm (F and H). (J–L) Serum liver function indices from the 4 groups: ALT (J), AST (K), and TBIL (L; n = 5). (M and N) Flow cytometry analysis of the effects of the 4 treatments on hepatic Th17 (M) and Treg cell proportions (n = 5) (N). Data are mean ± SD. Kruskal-Wallis H-test with Dunn’s post hoc test for F and I; 1-way ANOVA with Bonferroni’s post hoc analysis for other comparisons. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. The experiments for C–E were each repeated 3 times.