Integrated multi-omics identifies distinct macrophage alterations during progression of metabolic dysfunction-associated steatohepatitis
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. This study uses multi-omics approaches to dissect the roles of macrophage populations in the progression of metabolic dysfunction-associated steatohepatitis. GPNMB+ macrophages accumulate in the portal tract in advanced disease and may have antigen-presenting capabilities.
Authors
- Rita Feio‐Azevedo (ORCID: https://orcid.org/0000-0002-4091-1402)
- Ann K. Daly (ORCID: https://orcid.org/0000-0002-7321-0629)
- James Clark (ORCID: https://orcid.org/0000-0002-7888-5684)
- Markus Boesch (ORCID: https://orcid.org/0000-0003-2483-9583)
- Olivier Govaere (ORCID: https://orcid.org/0000-0002-4426-6930)
- Thierry Voet (ORCID: https://orcid.org/0000-0003-1204-9963)
- Jef Verbeek (ORCID: https://orcid.org/0000-0002-1549-8003)
- Francesca Bosisio (ORCID: https://orcid.org/0000-0002-4059-139X)
- Ellen Deleus (ORCID: https://orcid.org/0000-0002-8496-7723)
- Lukas Van Melkebeke (ORCID: https://orcid.org/0000-0003-0361-1176)
- Frederik De Smet (ORCID: https://orcid.org/0000-0002-6669-3335)
- Gautam Shankar (ORCID: https://orcid.org/0000-0001-5188-2152)
- Quentin M. Anstee (ORCID: https://orcid.org/0000-0002-9518-0088)
- Hannelie Korf (ORCID: https://orcid.org/0000-0003-3540-0138)
- Baki Topal (ORCID: https://orcid.org/0000-0002-2687-7535)
- Caitlyn Myers (ORCID: https://orcid.org/0000-0001-5755-2525)
- Tessa Ostyn
- Joris Jaekers (ORCID: https://orcid.org/0000-0001-5101-4574)
- T Roskams
- Anetta Härtlová (ORCID: https://orcid.org/0000-0002-8152-4361)
- Nikolina Dubroja Lakic
- Lena Smets (ORCID: https://orcid.org/0000-0001-8554-6616)
- Bram Boeckx (ORCID: https://orcid.org/0000-0002-0296-6680)
- Matthias Lannoo (ORCID: https://orcid.org/0000-0001-7815-1157)
- Halit Topal (ORCID: https://orcid.org/0000-0002-5869-6296)
- Simon Cockell
- Trieu My Van
- Dania El Abyad (ORCID: https://orcid.org/0009-0004-2083-0236)
- Najmeh Saffarzadeh
- C V Schneider
- J Chui
- Schalk van der Merwe
- Seray Anak
- Mattias Ekstedt (ORCID: https://orcid.org/0000-0002-5590-8601)
- Daniel Newhouse
- Jeremy Palmer
- Elisabetta Bugianesi
- Michele Vacca (ORCID: https://orcid.org/0000-0002-1973-224X)
- Asier Antoranz (ORCID: https://orcid.org/0000-0001-7284-610X)
- Jerome Boursier
- Michael Allison (ORCID: https://orcid.org/0000-0003-3677-3294)
- Diether Lambrechts (ORCID: https://orcid.org/0000-0002-3429-302X)
- Vlad Ratziu
- Jörn M. Schattenberg (ORCID: https://orcid.org/0000-0002-4224-4703)
- Kai Markus Schneider
- Dina Tiniakos (ORCID: https://orcid.org/0000-0003-4657-7780)
- Paula Longás Calvo
- Sven Francque
Institutions
- Linköping University (SE)
- University of Antwerp (BE)
- Bruker (United States) (US)
- National and Kapodistrian University of Athens (GR)
- Universitair Ziekenhuis Leuven (BE)
- University Medical Center Freiburg (DE)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Foundation for Liver Research (GB)
- Sorbonne Université (FR)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Antwerp University Hospital (BE)
- VIB-KU Leuven Center for Microbiology (BE)
- Newcastle upon Tyne Hospital (GB)
- NIHR Newcastle Biomedical Research Centre (GB)
- Fondation pour l’innovation en Cadiométabolisme et Nutrition (FR)
- University Hospital Carl Gustav Carus (DE)
- Université d'Angers (FR)
- University of Turin (IT)
- University of Bari Aldo Moro (IT)
- Technische Universität Dresden (DE)
- Newcastle University (GB)
- University of Gothenburg (SE)
- RWTH Aachen University (DE)
- Saarland University (DE)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Genetics
- Published
- 2026-05-18
- DOI
- https://doi.org/10.1038/s41588-026-02600-3
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fonds Wetenschappelijk Onderzoek
- Innovative Medicines Initiative