Cordycepin targets HDAC7 to mediate epithelial-mesenchymal transition to ameliorate pulmonary fibrosis
Cordycepin(Cpn),a natural active compound derived from the traditional Chinese medicine Cordyceps sinensis,has antifibrotic,antioxidant,and anti-inflammatory effects,but the impact of Cpn on pulmonary fibrosis and the downstream molecular mechanism remain unclear.In this study,A549 cells were induced by transforming growth factor βl(TGFβ1)in vitro,the viability of A549 cells was evaluated by CCK-8 assay;and migration of A549 cells were detected by wound healing assay,invasion of A549 cells were detected by transwell assay.Molecular docking and molecular dynamics simulations were used to predict the interaction of histone deacetylase 7(HDAC7)with vimentin and the association of Cpn with HDAC7.The pulmonary fibrosis model of mice was established by bleomycin in vivo to investigate the effect of Cpn on pathological changes of lung tissue.The impact of Cpn and molecular mechanism on pulmonary fibrosis were studied by Western blot assay,cell transfection assay,immunoprecipitation assay,immunofluorescence assay,immunohistochemistry and real-time quantitative PCR(RT-qPCR).All animal experiments were approved by the Shanghai Children's Medical Center Experimental Animal Ethics Committee(grant No.SCMC-LAWEC-2022-017).Results showed that Cpn had no toxic effect on A549 cells even at the concentration of 100 μmol·L-1.Cpn inhibited migration and invasion of A549 cells and reduced deposition of collagen,the degree of lung inflammation and fibrosis in mice;in vivo and in vitro models,Cpn significantly reversed mRNA and protein expressions of epithelial-mesenchymal transition(EMT)and lung fibrosis markers collagen Ⅰ,α-smooth muscle actin(α-SMA),N-cadherin,vimentin and E-cadherin and HDAC7.Deficiency of HDAC7 suppressed TGFβ1-induced EMT and expression of collagen Ⅰ;vimentin interacted with HDAC7;and molecular docking experiment revealed that Cpn was interrelated with HDAC7.In conclusion,Cpn can target HDAC7 to mediate EMT and exert its anti-fibrotic effect,the inhibition of EMT and the improvement of pulmonary fibrosis provide a new idea and choice for the development of anti-pulmonary fibrosis drug.
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