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

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.