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© 2021 Federation of European Biochemical SocietiesHeme is an iron–containing complex involved in fundamental cellular functions including oxygen transport. Free heme accumulation in blood, during intravascular hemolysis and other pathological conditions, triggers vascular dysfunction, pro–inflammatory, and prothrombotic cascade. Studies by May et al present a novel finding that heme is a ligand for RAGE and that heme binds to the V domain of RAGE and induces RAGE oligomerization. Furthermore, they show that the in vivo consequences of heme–RAGE interaction lead to a pro–inflammatory and procoagulant phenotype in the lungs. This discovery of heme as a ligand for RAGE sets the stage for probing the role of RAGE in heme homeostasis and the pathogenic role of heme–RAGE interaction in hemolytic diseases.
