Understanding and targeting erythroid cell metabolism

Red blood cell (RBC) production, or erythropoiesis, serves as a paradigm for studying cellular differentiation in both physiological and pathological contexts. While the transcriptional and epigenetic programs controlling erythropoiesis are well characterized, the metabolic regulation of this complex process remains underexplored. Recent discoveries that pyruvate kinase activators improve outcomes in sickle cell disease and thalassemia underscore the therapeutic potential of targeting metabolism in RBC disorders. However, further progress is limited by an incomplete understanding of the metabolic networks supporting erythropoiesis and RBC function. This review highlights emerging insights into erythroid metabolic reprogramming involving bioenergetic and biosynthetic processes, newly discovered pathways shaping the erythroid metabolome, and the promise and challenges of exploiting metabolic vulnerabilities in inherited and acquired red cell disorders.