Heterogeneity of hepatic macrophages in MASLD/MASH: Lipid-associated programs, molecular mechanisms, spatial niches, and therapeutic implications

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are leading causes of chronic liver disease worldwide. Increasing evidence indicates that hepatic macrophages play central roles in disease development and resolution. However, their functional heterogeneity has only recently been recognized. Hepatic macrophages consist of embryonically derived Kupffer cells and monocyte-derived macrophages, which undergo dynamic phenotypic and metabolic remodeling in response to lipid overload, inflammation, and tissue injury. Recent single-cell, spatial, and multi-omics studies have identified lipid-associated macrophages (LAMs) as a distinct macrophage program enriched in MASLD/MASH. LAMs are characterized by enhanced lipid-handling capacity, lysosomal activation, and lipid-sensing transcriptional programs involving triggering receptor expressed on myeloid cells 2 (TREM2), peroxisome proliferator-activated receptor γ, liver X receptor α, and microphthalmia-associated transcription factor. Spatially, TREM2⁺ LAMs localize to steatotic and fibrotic niches, where local lipid and inflammatory cues shape their chromatin accessibility and functional states. This heterogeneity enables divergent roles in inflammation, metabolic regulation, fibrogenesis, and disease resolution, offering opportunities for stage-specific therapeutic intervention. This review summarizes the understanding of hepatic macrophage heterogeneity in MASLD/MASH, with a focus on lipid-associated programs, molecular mechanisms, spatial organization, and functional plasticity across disease stages. We also discuss emerging therapeutic strategies targeting specific macrophage subsets and pathways, and highlight the need for spatiotemporally precise modulation of macrophage functions in future therapeutic development.