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The medical fungus Hirsutella sinensis has been used as a Chinese folk health supplement because of its immunomodulatory properties.Our previous studies established the antifibrotic action of Hirsutella sinensis mycelium (HSM) in the lung.The epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of idiopathic pulmonary fibrosis.The present study investigates the role of HSM in mediating EMT during the development of pulmonary fibrosis.HSM significantly inhibits bleomycin (BLM)-induced pulmonary fibrosis by blocking the EMT.In addition,the expression levels of midkine are increased in the lungs of the BLM-induced group.Further analysis of the results indicates that the mRNA level of midkine correlated positively with EMT.HSM markedly abrogates the transforming growth factor β-induced EMT-like phenotype and behavior in vitro.The activation of midkine related signaling pathway is ameliorated following HSM treatment,whereas this extract also caused an effective attenuation of the induction of EMT (caused by midkine overexpression) in vitro.Results further confirm that oral medication of HSM disrupted the midkine pathway in vivo.Overall,findings suggest that the midkine pathway and the regulation of the EMT may be considered novel candidate therapeutic targets for the antifibrotic effects caused by HSM.