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 5

STING/NF-κB suppresses Treg skewing by blocking AP-1–mediated BMP4 transcription.

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STING/NF-κB suppresses Treg skewing by blocking AP-1–mediated BMP4 trans...
(A) ELISA detecting BMP4 protein in Stingfl/fl and StingΔEC livers (n = 5). (B) FACS analysis of Treg differentiation from primary naive CD4+ T cells induced by indicated cytokines (n = 5). (C) TFs of BMP2/4/6 predicted by the NetworkAnalyst platform. (D) qPCR analyzing Bmp4 transcription in primary LSECs treated with TNF-α or vehicle (n = 3). (E) Dual-luciferase reporter assay evaluating transcriptional regulation of BMP4 by NF-κB subunits (n = 6). (F) Predicted p65 binding motif and sites within the BMP4 promoter using the JASPAR database. (G) Schematic of predicted p65 binding sites and targeted primers. (H) ChIP-qPCR validating p65 binding to the BMP4 promoter (fragment –1,146 to –1,004) (n = 3). (I) Schematic of LSEC-mediated Treg differentiation. (J) qPCR analyzing Bmp4 transcription in LSECs from Stingfl/fl and StingΔEC mice treated with TNF-α or vehicle (n = 3). (K and L) FACS and quantification of Treg differentiation induced by the indicated LSEC-conditioned medium (n = 3). (M) Predicted binding motifs and sites of p65 and AP-1 (including c-Fos and c-Jun) within the BMP4 promoter using the JASPAR database. (N) ChIP-qPCR detection of AP-1 binding to the BMP4 promoter (fragment –1,146 to –1,004) with or without p65 (n = 3). (O) Dual-luciferase reporter assay evaluating transcriptional regulation of BMP4 by AP-1 with or without p65 (n = 3). (P) qPCR analyzing Bmp4 transcription in endothelial cells transfected with AP-1 and/or p65 (n = 3). (Q) qPCR analyzing Bmp4 transcription in LSECs from Stingfl/fl and StingΔEC mice treated with T-5224 or vehicle (n = 3). Data are mean ± SD. Two-tailed Student’s t test for A, B, D, and H; 1-way ANOVA with Bonferroni’s post hoc analysis for other comparisons. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.