Markus Boesch, Seray Anak, Dania El Abyad, Tessa Ostyn, Asier Antoranz, Trieu My Van, Daniel Newhouse, Caitlyn Myers, Lukas Van Melkebeke, Jeremy Palmer, Najmeh Saffarzadeh, J Chui, Rita Feio‐Azevedo, Lena Smets, Gautam Shankar, Nikolina Dubroja Lakic, Paula Longás Calvo, Thierry Voet, James Clark, Simon Cockell, Matthias Lannoo, Ellen Deleus, Joris Jaekers, Halit Topal, Baki Topal, Kai Markus Schneider, Michele Vacca, Michael Allison, Mattias Ekstedt, Jerome Boursier, Elisabetta Bugianesi, Vlad Ratziu, Frederik De Smet, Bram Boeckx, Ann K. Daly, Jörn M. Schattenberg, Jef Verbeek, Francesca Bosisio, Diether Lambrechts, T Roskams, C V Schneider, Sven Francque, Hannelie Korf, Anetta Härtlová, Dina Tiniakos, Quentin M. Anstee, Schalk van der Merwe, Olivier Govaere
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.