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

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.