Hemasphere. 2026 Jan;10(1):
e70297
Erythropoiesis is a finely regulated process ensuring continuous red blood cell production to maintain oxygen delivery. Disruptions in this process give rise to defective erythropoiesis, characterized by impaired lineage commitment and progenitor development, and ineffective erythropoiesis (IE), marked by expansion of erythroid progenitors with intramedullary apoptosis of late precursors. These abnormalities underlie anemia in diverse hematological disorders, including β-thalassemia, sickle cell disease (SCD), myelodysplastic syndromes (MDSs), and emerging entities such as vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS). This review synthesizes recent insights into the molecular regulators of erythropoiesis, emphasizing the roles of GATA1, its chaperone HSP70, caspase activity, and extrinsic signals such as growth differentiation factor 11 (GDF11) and inflammatory cytokines. We highlight how globin-chain imbalance, inflammasome activation, oxidative stress, and clonal mutations converge on common pathways that disrupt erythroid maturation. Advances in therapy now directly target these mechanisms: Luspatercept, a TGF-β ligand trap, has transformed care in β-thalassemia and MDS by restoring late-stage differentiation, while anti-inflammatory strategies, metabolic modulators, and gene editing approaches are being actively explored. Together, these discoveries reframe IE as a modifiable process rather than an inevitable consequence of disease. By distinguishing defective from IE and mapping their mechanistic underpinnings, this review outlines how novel therapeutic strategies can improve anemia, reduce systemic complications, and ultimately enhance outcomes in patients with erythroid disorders.