An MMP12-Enriched Kupffer Cell-Associated Programme Links ATF3-Associated Immunometabolic Remodeling to Hepatic...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver injury, yet the cellular programmes linking metabolic stress with inflammation and fibrosis remain incompletely understood. Here, we integrated single-cell transcriptomics, regulatory network analysis, functional validation, and in vivo perturbation approaches to investigate macrophage-associated mechanisms during metabolic liver injury. We identified an MMP12-enriched Kupffer cell-associated programme that emerges under metabolic stress and exhibits distinct ATF3-associated immunometabolic characteristics. Functional modulation of ATF3 altered macrophage transcriptional states and mitochondrial metabolic properties, supporting its involvement in macrophage adaptation. Intercellular communication analysis combined with experimental validation identified CD93-associated hepatocyte responses and FLRT2-associated hepatic stellate cell activation as candidate pathways linking macrophage states with steatosis and fibrotic remodeling. Hepatic perturbation of these pathways improved metabolic and fibrosis-related phenotypes, while additional analyses defined the interpretation of AAV8-mediated effects at the hepatic pathway level rather than exclusive Kupffer cell specificity. Human liver datasets provided exploratory evidence for conservation of macrophage-associated regulatory programmes. Collectively, our findings reveal an immunometabolic framework connecting macrophage states with hepatic metabolic dysfunction and tissue remodeling, providing potential insights for precision therapeutic strategies in MASLD.