Bone marrow(BM) endothelial progenitor cell(EPC) damage with unknown mechanism delays the repair of endothelial cells(ECs) and hematopoiesis recovery after chemo-radiotherapy. Herein, enhanced glycolytic enzyme PFKFB3 was demonstrated in the damaged BM EPCs of patients with poor graft function(PGF), a clinical model of EPC damage-associated poor hematopoiesis after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Moreover, glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one(3PO) alleviated the damaged BM EPCs of PGF patients in vitro. Consistently, PFKFB3 overexpression triggered BM EPC damage after 5FU treatment and impaired hematopoiesis-supporting ability in vitro. Mechanismly, PFKFB3 facilitated pro-apoptotic transcription factor FOXO3A and its downstream gene expressions, including p21, p27, FAS after 5FU treatment in vitro. Moreover, PFKFB3 induced NF-κB activation and its downstream adhesion molecule E-selectin expression, while reduced hematopoietic factor SDF-1 expression, which could be rescued by FOXO3A silence. Highly expressed PFKFB3 was found in damaged BM ECs of chemo-radiotherapy-induced myelosuppression murine models. Furthermore, the BM EC-specific PFKFB3 overexpression murine model demonstrated that PFKFB3 aggravated BM EC damage, and impaired hematopoiesis recovery after chemotherapy in vivo, which could be improved by 3PO, indicating a critical role of PFKFB3 in regulating BM EC damage. Clinically, PFKFB3-induced FOXO3A expression and NF-κB activation were confirmed to contribute to the damaged BM EPCs of patients with acute leukemia after chemotherapy. 3PO repaired the damaged BM EPCs by reducing FOXO3A expression and phospho-NF-κB p65 in patients after chemotherapy. In summary, our results reveal a critical role of PFKFB3 in triggering BM EPC damage and indicate that endothelial-PFKFB3 may be a potential therapeutic target for myelosuppressive injury.
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