Erythrophagocytes in hemolytic anemia, wound healing, and cancer

Hemolysis is a ubiquitous pathology defined as premature red blood cell destruction within the circulation or local tissues. One of the most archetypal functions of macrophages is phagocytosis of damaged or extravasated red blood cells, preventing the extracellular release of toxic hemoglobin and heme. Upon erythrophagocytosis, spiking intracellular heme concentrations drive macrophage transformation into erythrophagocytes, leveraging antioxidative and iron recycling capacities to defend against hemolytic stress. This unique phenotype transformation is coordinated by a regulatory network comprising the transcription factors BACH1, SPI-C, NRF2, and ATF1. Erythrophagocytes negatively regulate inflammation and immunity and may modulate disease-specific outcomes in hemolytic anemia, wound healing, atherosclerosis, and cancer. In this opinion article, we outline the known and presumed functions of erythrophagocytes and their implications for therapeutic innovation and research. Macrophages are the central hub for the detoxification of oxidative hemoglobin and heme. This protective function progresses either via engulfment and controlled degradation of red blood cells (RBCs) or via receptor-mediated clearance of RBC toxins.Intracellular heme signaling via BACH1, SPI-C, NRF2, and ATF1 orchestrates macrophage transformation into specialized erythrophagocytes with optimized antioxidant and iron recycling capacity.Novel discoveries demonstrated that erythrophagocytes have a unique anti-inflammatory phenotype with a disease- and context-dependent modulator effect on host defense, wound healing, atherosclerosis, and cancer progression.Enhancement or targeted suppression of erythrophagocyte functions may be exploited as novel therapeutic strategies.