biostudies-literatureGuilliams MEuropean Research CouncilWellcome Trust379-396.e38https://www.ebi.ac.uk/biostudies/studies/S-EPMC8809252biostudies-literatureUnknown185(2)The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human and murine liver combining single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells, including a population of lipid-associated macrophages (LAMs) at the bile ducts. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and LAMs. We also uncover the respective spatially resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demoCellSpatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.PMC8809252107364/Z/15/Z851908Hoorens AMartens LZwicker CDevriendt BWillaert ASaelens WVanlander AVan Nieuwenhove YKaptein SJFThone TBujko ABrowaeys RWittamer VDe Ponti FFBerrevoet FGuilliams MVanneste BWagner CTen Dijke PHaest BRemmerie ADallmeier KScott CLVanhalewyn TLippens SGoncalves AFerrero GDeplancke BVanderborght BDevisscher LNeyts JSvedberg FRCox ESaeys YVan Vlierberghe HBonnardel JCasaert SGeldhof PfalseSpatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human and murine liver combining single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells, including a population of lipid-associated macrophages (LAMs) at the bile ducts. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and LAMs. We also uncover the respective spatially resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demo2022-01-01T00:00:00Z2022 Jan2026-06-19T03:08:01.647Z2025-04-07T04:46:23.075ZS-EPMC88092523502106310.1016/j.cell.2021.12.018