Ferroptosis-driven metabolic reprogramming in macrophages: Reshaping glucose utilization landscapes

ABSTRACT: Ferroptosis, an iron-dependent form of programmed cell death, has attracted significant attention in the field of immunometabolism. Macrophages, which are key immune cells, undergo metabolic reprogramming and polarization, influencing disease progression. This review investigates the interplay between ferroptosis signaling and macrophage glycometabolic reprogramming. To this end, it highlights the roles of iron, lipid, and amino acid metabolism in ferroptosis, alongside the distinct glycometabolic pathways in M1 and M2 macrophages. It also examines how gluconeogenesis, lactate, nicotinamide adenine dinucleotide phosphate, glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway regulate ferroptosis. Furthermore, the review investigates the feedback mechanisms between macrophage polarization and ferroptosis signaling and discusses the implications of these interactions in diseases such as cancer, metabolic disorders, infections, neurodegenerative conditions, and cardiovascular diseases. Finally, it proposes therapeutic strategies targeting ferroptosis to modulate macrophage polarization, offering new insights for disease treatment. Thus, this work provides a foundation for understanding ferroptosis-macrophage metabolism interactions and identifies potential therapeutic targets.