Revisiting macrophage metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: mechanisms, regulation, and therapeutic breakthroughs

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults globally, yet therapeutic options remain limited. Macrophage metabolic reprogramming is increasingly recognized as an important contributor to disease progression. Hepatic macrophages from resident Kupffer cells (KCs) to infiltrating monocyte-derived macrophages (MoMFs) and triggering receptor expressed on myeloid cells 2 (TREM2) + lipid-associated macrophages (LAMs) shift their bioenergetic profile from fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) toward aerobic glycolysis. This review maps the metabolic circuits driving macrophage-mediated inflammation in MASLD. We delineate how tricarboxylic acid (TCA) cycle disruption generates signaling metabolites that enforce glycolytic commitment through hypoxia-inducible factor stabilization, how metabolic-epigenetic coupling perpetuates inflammatory programs, and how the failure of repair mechanisms and mitochondrial quality control accelerates tissue damage. Notably, the IRG1-itaconate axis exhibits a dynamic U-shaped trajectory across MASLD stages: itaconate levels decrease during early steatosis due to Kupffer cell loss, but subsequently rise markedly during MASH as infiltrating macrophages upregulate IRG1 expression, representing a compensatory yet insufficient anti-inflammatory response. We further examine how these metabolic states evolve across disease stages, from simple steatosis through steatohepatitis and fibrosis to cirrhosis, and assess the therapeutic potential of metabolic interventions. Recent FDA accelerated approvals of resmetirom and semaglutide for selected adults with non-cirrhotic MASH and F2-F3 fibrosis have expanded the therapeutic landscape. Their clinical benefits are primarily supported by histological endpoints; whether modulation of hepatic macrophage metabolism contributes directly to these benefits remains to be established. Emerging evidence indicates that macrophage metabolic states retain plasticity and can be pharmacologically reprogrammed, with single-cell metabolomics poised to guide precision therapeutic strategies.