Advertisement

ResearchIn-Press PreviewHepatologyMetabolism Open Access | 10.1172/JCI207031

Metabolic stress-activated endothelial STING rewires the sinusoidal immune niche in MASLD

Zhi-Bin Lin,1 Peng Zou,1 Xian-Yi Ma,1 Jun-Bo Song,1 Hong Zhang,1 Wei Du,1 Dan Wei,1 Ping Song,1 Xin Hong,1 Jingjing Liu,1 Zhi-Qiang Fang,1 Hao Xu,1 Fei He,1 Juan-Li Duan,1 Ke-Feng Dou,1 and Lin Wang1

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Lin, Z. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Zou, P. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Ma, X. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Song, J. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Zhang, H. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Du, W. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Wei, D. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Song, P. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Hong, X. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Liu, J. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Fang, Z. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Xu, H. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by He, F. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Duan, J. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Dou, K. in: PubMed | Google Scholar

1Department of Hepatobiliary Surgery, Fourth Military Medical University, Xi’an, China

Find articles by Wang, L. in: PubMed | Google Scholar

Published August 12, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI207031.
Copyright © 2026, Lin et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 12, 2026 - Version history
View PDF
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 reveals stage-dependent activation of the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling in LSEC comparable to that in macrophage, with endothelial activation showing greater responsiveness to metabolic stress. Endothelial-specific STING deletion attenuates steatohepatitis and fibrosis in mice. Mechanistically, LSEC-intrinsic STING activation reprograms the angiocrine landscape through NF-κB-mediated transcriptional repression of the endothelial-derived factor BMP4. Loss of BMP4 disrupts 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 correlates with BMP4 expression at single-cell resolution. Targeted delivery of a STING inhibitor to LSECs using peptide-functionalized nanoparticles restores hepatic metabolic-immune 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.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

Version history
  • Version 1 (August 12, 2026): In-Press Preview
Advertisement
Advertisement