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Lookup NU author(s): James Clark, Dr Simon CockellORCiD, Emerita Professor Ann Daly, Professor Dina Tiniakos, Professor Quentin AnsteeORCiD, Dr Lizah Van der AartORCiD, Dr Olivier Govaere
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© The Author(s) 2026. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition impacting over 30% population, yet the dynamic changes in macrophage composition from steatosis to steatohepatitis (metabolic dysfunction-associated steatohepatitis, MASH) remain unclear. Here, by integrating single-nucleus transcriptomics, spatial multi-omics and proteomics on human samples, we delineate the evolving landscape of hepatic macrophages across the MASLD spectrum. Our analysis reveals a progressive depletion of Kupffer cells accompanied by the emergence of diverse, phenotypically distinct macrophage subsets. Spatial multi-omics further demonstrates that disease progression toward MASH is marked by an accumulation of antigen-presenting, phagocytic GPNMB+ macrophages, supported by IL32-producing hepatocytes. These macrophages showed an adaptive metabolic and pro-inflammatory phenotype that is tightly regulated by both spatial context and disease stage. Identified macrophage markers enable patient stratification by disease activity and its stage across independent clinical cohorts. Our study sheds light on the diversity of macrophage identities and metabolic-adaptive phenotypes during the progression of MASLD.
Author(s): Boesch M, Anak S, El Abyad D, Ostyn T, Antoranz A, My Van T, Newhouse D, Myers C, Van Melkebeke L, Palmer J, Saffarzadeh N, Chui JS-H, Feio-Azevedo R, Smets L, Shankar G, Dubroja Lakic N, Calvo PL, Voet T, Clark J, Cockell S, Lannoo M, Deleus E, Jaekers J, Topal H, Topal B, Schneider KM, Vacca M, Allison M, Ekstedt M, Boursier J, Bugianesi E, Ratziu V, De Smet F, Boeckx B, Daly AK, Schattenberg JM, Verbeek J, Bosisio F, Lambrechts D, Roskams T, Schneider CV, Francque S, Korf H, Hartlova A, Tiniakos D, Anstee QM, van der Merwe S, Govaere O
Publication type: Article
Publication status: Published
Journal: Nature Genetics
Year: 2026
Pages: Epub ahead of print
Online publication date: 18/05/2026
Acceptance date: 14/04/2026
ISSN (print): 1061-4036
ISSN (electronic): 1546-1718
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41588-026-02600-3
DOI: 10.1038/s41588-026-02600-3
PubMed id: 42151416
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