Ziyuglycoside II ameliorates chemotherapy-induced neutropenia by promoting neutrophil differentiation and functional recovery via SPI1/CEBPE transcriptional regulation
Background: Chemotherapy-induced neutropenia (CIN) remains the major dose-limiting toxicity of myelosuppressive regimens, and the discovery of therapeutic approaches that can effectively restore neutrophil production and function could address this clinical issue. ZGS II, a bioactive compound extracted from Sanguisorba officinalis, has shown potential in improving leukopenia. To further validate its therapeutic potential for CIN, its underlying mechanisms must be elucidated. Therefore, this study aims to evaluate the efficacy of ZGS II in alleviating neutropenia and myelosuppression induced by cyclophosphamide and to elucidate its underlying mechanism through transcriptome sequencing, protein-protein interaction analysis, and functional validation methods.Methods: Cyclophosphamide-induced neutropenia mice model and human promyelocytic leukemia cell line NB4 model was used to evaluate the effects of ZGS II alleviating CIN and promoting neutrophil differentiation, through blood cell count, flow cytometry analysis, and Wright-Giemsa staining. The specific molecular mechanism of ZGS II in treating CIN was comprehensively analyzed by transcriptomics, computational simulations and in vivo function verification.Results: This study demonstrated that ZGS II effectively alleviates cyclophosphamide-induced neutropenia and bone marrow suppression in mice, promoting neutrophil reconstitution without excessive marrow mobilization. Transcriptomic analysis revealed that ZGS II restores neutrophil-related transcriptional programs, enhancing leukocyte migration, myeloid activation, and inflammatory regulation pathways. Integration of public granulopoiesis data identified 37 key genes associated with neutrophil differentiation and maturation. Mechanistically, ZGS II directly bound transcriptional regulators SPI1 and CEBPE, restoring their protein expression and promoting granulocytic differentiation. Furthermore, functional assays confirmed that ZGS II enhanced neutrophil phagocytosis, ROS production and cytokine balance. Critically, ZGS II administration conferred significant survival advantages in neutropenic mice challenged with Staphylococcus aureus.Conclusions: Our study demonstrates that ZGS II alleviates CIN by transcriptional regulation via SPI1/CEBPE to promote neutrophil differentiation and functional recovery. These findings elucidate ZGS II as a promising therapeutic agent for CIN through transcriptional regulation of neutrophil maturation and function.