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Here, we integrate single-cell RNA sequencing, spatial transcriptomics, high-dimensional spectral flow cytometry, and metabolomics to resolve the hepatic immune landscape following I\/R at cellular and spatial resolution. While confirming extensive immune remodeling, we identify a dominant neutrophil\u2013Kupffer cell communication axis mediated by neutrophil-derived thrombospondin-1 (TSP-1), which selectively engages CD36 on Kupffer cells. This interaction drives coordinated immune-metabolic reprogramming in Kupffer cells, characterized by suppression of oxidative phosphorylation, enhanced glycolysis, and remodeling of sphingolipid metabolism, including accumulation of hexosylceramides. Spatial analyses reveal preferential neutrophil\u2013Kupffer cell colocalization within necrotic niches, and cross-species integration with human liver transplant datasets demonstrates conserved upregulation of the TSP-1\/CD36 axis following reperfusion. Pharmacologic inhibition of TSP-1 attenuates liver injury and inflammatory responses in vivo. Together, these findings define a spatially organized, neutrophil-driven immune-metabolic circuit that governs functional reprogramming of Kupffer cells during surgical stress and identify the TSP-1\/CD36 pathway as a conserved and targetable mediator of sterile liver injury.<\/jats:p>","DOI":"10.1172\/jci.insight.203495","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:01:08Z","timestamp":1790013668000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrated single-cell multiomics reveals neutrophil-driven immune-metabolic reprogramming of Kupffer cells via thrombospondin-1\/CD36 after surgical stress"],"prefix":"10.1172","volume":"11","author":[{"given":"Hongji","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Virginia, Charlottesville, Virginia, 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