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Ethnopharmacological relevance Fufang E'jiao Jiang (FEJ), a famous traditional Chinese medicine formula from “Liangyi Ointment”, consists of five crude drugs, Colla corii asini, Radix Ginseng Rubra, Radix Rehmanniae Preparata, Codonopsis pilosula, and Crataegus pinnatifida Bge. It has pronounced functions of qi-nourishing and blood-activating. Recently, it has been widely used in China as a medication against myelosuppression in cancer treatment. Aim of the study We aimed to investigate the complex mode of action and underlying mechanisms of Fufang E'jiao Jiang (FEJ) regarding its hematopoietic effect. Main methods Mice were divided into 5 groups of control, model, high dose FEJ (HFEJ), medium dose FEJ (MFEJ) and low dose FEJ (LFEJ). After 10 days from the administration, bone marrow cells (BMCs) were extracted for nucleated cells counts, flow cytometry analysis of hematopoietic stem cells (HSCs) population, as well as hematopoietic progenitor cells (HPCs) colony-forming unit (CFU) assay. A portion of bone marrow nucleated cells (BMNCs) of MFEJ group were prepared for RNA sequencing (RNA-Seq). The transcriptome data were analyzed based on the differentially expressed genes (DEGs). The molecular mechanisms of FEJ were deducted based on the biological processes and protein-protein interaction (PPI) network. Results FEJ could significantly increase the percentage of HSCs and the quantities of BFU-E and CFU-GM in BMSCs. FEJ could stimulate the proliferation of HSC and the differentiation of HPC to all lineages, which may thereby accelerate the recovery of hematopoietic function in myelosuppressive mice. By providing transcriptome profile we highlighted several genes and biological processes that might be applicable for FEJ to treat chemotherapy-induced myelosuppression. GO analysis showed that the co-expressed DEGs in FEJ vs model and model vs control group were involved in biological processes including ossification, osteoblast differentiation, bone mineralization and bone development. The KEGG pathway analysis pointed out ECM-receptor interaction and PI3K-AKT signaling pathway as the most relevant pathways to the function of FEJ on myelosuppression. PPI network showed MMP2 and COL1A1 were the relatively large nodes. Conclusion FEJ has the hematopoietic effect in chemotherapy-induced myelosuppression mice. It might be achieved by improving the proliferative capacity of HSCs and the differentiation ability of HPCs. The molecular mode of action of FEJ might be the improvement of the bone marrow microenvironment via ECM-receptor interaction, the promoted proliferation of HSC through regulation of PI3K-AKT signaling pathway, and the involvement of osteoblasts and osteoclasts. MMP2 and COL1A1 appear to be the key relevant regulatory molecules. These results provide significant insight into the hematopoietic effects of FEJ in myelosuppression and point out novel targets for future validating analyses.