Optimising Haematopoietic Stem Cell Transplantation: Enhancing Myeloablation Sensitivity and Alleviating Anaemia Using Roxadustat ( FG ‐4592)

Haematopoietic stem cell transplantation (HSCT) is an effective therapy for a broad range of hematologic, autoimmune and genetic diseases. Successful HSCT requires adequate myeloablation to create space in the bone marrow microenvironment for donor haematopoietic stem and progenitor cells. Standard conditioning with busulfan and cyclophosphamide (BuCy), although widely used, may not completely clear recipient cells and can cause significant toxicity. Roxadustat (FG‐4592), a hypoxia‐inducible factor prolyl hydroxylase inhibitor used to treat renal anaemia, modulates HIF‐1α stability and influences erythropoiesis, iron metabolism and cellular stress responses. Here, we investigated whether co‐administration of FG‐4592 during BuCy conditioning improves myeloablation efficiency and enhances donor‐cell engraftment. Our results show that FG‐4592 increases the sensitivity of bone marrow mononuclear cell (BM‐MNC) populations to BuCy conditioning, promoting deeper depletion of both haematopoietic and non‐haematopoietic recipient cells. This improved clearance supports enhanced donor‐cell residency following transplantation. Furthermore, in β 654 thalassaemia mice, FG‐4592 alleviated anaemia and reduced splenic iron deposition after HSCT. These findings suggest that FG‐4592 can serve as an effective adjuvant to standard myeloablation regimens, supporting improved engraftment and hematologic recovery. To our knowledge, this is the first study demonstrating that a HIF‐PH inhibitor can enhance conditioning efficiency during HSCT.