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Peer-reviewedCC BY-NC-NDNature Genetics

Integrated multi-omics identifies distinct macrophage alterations during progression of metabolic dysfunction-associated steatohepatitis

  • Markus Boesch1,2,3,4
  • Seray Anak1
  • Dania El Abyad1
  • Tessa Ostyn1
  • Asier Antoranz1,2
  • Trieu My Van5
  • Daniel Newhouse5
  • Caitlyn Myers6
  • Lukas Van Melkebeke7,3
  • Jeremy M. Palmer8
  • Najmeh Saffarzadeh6
  • Jonathan Sai‐Hong Chui1,2
36 more authors
  • Rita Feio‐Azevedo3
  • Lena Smets3
  • Gautam Shankar1,2
  • Nikolina Dubroja1,2
  • Paula Longás Calvo2,4
  • Thierry Voet2,4
  • James A. Clark8
  • Simon Cockell8
  • Matthias Lannoo9
  • Ellen Deleus9
  • Joris Jaekers9
  • Halit Topal9
  • Baki Topal9
  • Kai Markus Schneider10,11,12,13
  • Michele Vacca14,15
  • Michael Allison16
  • Mattias Ekstedt17
  • Jérôme Boursier18
  • Elisabetta Bugianesi19
  • Vlad Ratziu20
  • Frederik De Smet1,2
  • Bram Boeckx21,22
  • Ann K. Daly8
  • Jörn Markus Schattenberg23
  • Jef Verbeek7,3
  • Francesca Maria Bosisio1,2
  • Diether Lambrechts21,22
  • Tania Roskams1
  • Carolin V. Schneider13
  • Sven Francque24,25
  • Hannelie Korf3
  • Anetta Härtlová26,6
  • DINA G. TINIAKOS27,8
  • Quentin Mark Anstee28,29
  • S Van der Merwe30,31
  • Olivier Govaere32,33,34
34 affiliations
  1. 1Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
  2. 2KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
  3. 3Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium
  4. 4Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium
  5. 5Bruker Spatial Biology, Seattle, WA, USA
  6. 6Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
  7. 7Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
  8. 8Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
  9. 9Department of Abdominal Surgery, UZ Leuven, Leuven, Belgium
  10. 10Center for Regenerative Therapies Dresden (CRTD), TUD Dresden University of Technology, Dresden, Germany
  11. 11Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, TUD Dresden University of Technology, Dresden, Germany
  12. 12Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany
  13. 13Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
  14. 14Clinica Medica 'C. Frugoni' and Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy
  15. 15Roger Williams Institute of Liver Studies, School of Immunology & Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Foundation for Liver Research and King's College Hospital, London, UK
  16. 16Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge NIHR Biomedical Research Centre, Cambridge, UK
  17. 17Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
  18. 18Hepatology Department, Angers University Hospital, Angers, France
  19. 19Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
  20. 20Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Sorbonne University, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
  21. 21Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
  22. 22VIB Center for Cancer Biology, Leuven, Belgium
  23. 23Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany
  24. 24Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
  25. 25Translational Research in Inflammation and Immunology (TWI2N), Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
  26. 26Institute of Medical Microbiology, Medical centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  27. 27Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
  28. 28Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK. [email protected]
  29. 29Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. [email protected]
  30. 30Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium. [email protected]
  31. 31Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, CHROMETA Department, KU Leuven, Leuven, Belgium. [email protected]
  32. 32Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium. [email protected]
  33. 33KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium. [email protected]
  34. 34Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. [email protected]
Open at sourceDOICite

Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{boesch2026integrated,
  title = {{Integrated multi-omics identifies distinct macrophage alterations during progression of metabolic dysfunction-associated steatohepatitis}},
  author = {Markus Boesch and Seray Anak and Dania El Abyad and Tessa Ostyn and Asier Antoranz and Trieu My Van and Daniel Newhouse and Caitlyn Myers and Lukas Van Melkebeke and Jeremy M. Palmer and Najmeh Saffarzadeh and Jonathan Sai‐Hong Chui and Rita Feio‐Azevedo and Lena Smets and Gautam Shankar and Nikolina Dubroja and Paula Longás Calvo and Thierry Voet and James A. Clark and Simon Cockell and Matthias Lannoo and Ellen Deleus and Joris Jaekers and Halit Topal and Baki Topal and Kai Markus Schneider and Michele Vacca and Michael Allison and Mattias Ekstedt and Jérôme Boursier and Elisabetta Bugianesi and Vlad Ratziu and Frederik De Smet and Bram Boeckx and Ann K. Daly and Jörn Markus Schattenberg and Jef Verbeek and Francesca Maria Bosisio and Diether Lambrechts and Tania Roskams and Carolin V. Schneider and Sven Francque and Hannelie Korf and Anetta Härtlová and DINA G. TINIAKOS and Quentin Mark Anstee and S Van der Merwe and Olivier Govaere},
  journal = {Nature Genetics},
  year = {2026},
  month = may,
  doi = {10.1038/s41588-026-02600-3},
  url = {https://hal.science/hal-05840385v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Integrated multi-omics identifies distinct macrophage alterations during progression of metabolic dysfunction-associated steatohepatitis
AU  - Markus Boesch
AU  - Seray Anak
AU  - Dania El Abyad
AU  - Tessa Ostyn
AU  - Asier Antoranz
AU  - Trieu My Van
AU  - Daniel Newhouse
AU  - Caitlyn Myers
AU  - Lukas Van Melkebeke
AU  - Jeremy M. Palmer
AU  - Najmeh Saffarzadeh
AU  - Jonathan Sai‐Hong Chui
AU  - Rita Feio‐Azevedo
AU  - Lena Smets
AU  - Gautam Shankar
AU  - Nikolina Dubroja
AU  - Paula Longás Calvo
AU  - Thierry Voet
AU  - James A. Clark
AU  - Simon Cockell
AU  - Matthias Lannoo
AU  - Ellen Deleus
AU  - Joris Jaekers
AU  - Halit Topal
AU  - Baki Topal
AU  - Kai Markus Schneider
AU  - Michele Vacca
AU  - Michael Allison
AU  - Mattias Ekstedt
AU  - Jérôme Boursier
AU  - Elisabetta Bugianesi
AU  - Vlad Ratziu
AU  - Frederik De Smet
AU  - Bram Boeckx
AU  - Ann K. Daly
AU  - Jörn Markus Schattenberg
AU  - Jef Verbeek
AU  - Francesca Maria Bosisio
AU  - Diether Lambrechts
AU  - Tania Roskams
AU  - Carolin V. Schneider
AU  - Sven Francque
AU  - Hannelie Korf
AU  - Anetta Härtlová
AU  - DINA G. TINIAKOS
AU  - Quentin Mark Anstee
AU  - S Van der Merwe
AU  - Olivier Govaere
PY  - 2026
DA  - 2026/05/18
JO  - Nature Genetics
DO  - 10.1038/s41588-026-02600-3
UR  - https://hal.science/hal-05840385v1
AB  - 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.
SN  - 1061-4036
SN  - 1546-1718
ER  -