通过网络药理学、机器学习及细胞实验探索泮托拉唑治疗特发性肺纤维化的分子机制OA

Objective To explore the molecular mechanism of pantoprazole in treating idiopathic pulmonary fibrosis(IPF)using network pharmacology,machine learning,molecular docking,and cellular experiments.Methods First,network pharmacology was employed to identify targets associated with IPF;common targets were obtained and used to construct a protein-protein interaction(PPI)network.Subsequently,machine learning was applied to screen core genes related to IPF prognosis,and a prognostic model was built based on these genes.The binding interactions between pantoprazole and key targets were analyzed via molecular docking.A549 cells were divided into a blank control group,a transforming growth factor-β1(TGF-β1)group,and pantoprazole sodium groups(20,40,and 60 mg/L).The TGF-β1 group was stimulated with 5 ng/mL TGF-β1 for 48 h;the pantoprazole sodium groups were co-stimulated with 5 ng/mL TGF-β1 and respective concentrations of pantoprazole sodium(20,40,and 60 mg/L)for 48 h.Western blot was used to detect the relative protein expression levels of epithelial-mesenchymal transition(EMT)-related markers,including E-cadherin,Vimentin,matrix metalloproteinase(MMP)1,and MMP8.Results Forty-one key targets of pantoprazole in the treatment of IPF were screened.Gene ontology and Kyoto encyclopedia of genes and genomes analyses indicated that pantoprazole was primarily involved in biological processes such as collagen catabolism and the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.Machine learning identified seven core targets:MMP1,MMP7,MMP8,kinase insert domain receptor,mitogen-activated protein kinase 8,serpin family A member 1,and sarcoma virus oncogene;an effective prognostic model for IPF was established based on these targets.Molecular docking demonstrated strong binding affinity between pantoprazole and these targets.Cellular experiments revealed that pantoprazole reversed TGF-β1 induced EMT in A549 cells,as evidenced by up regulated E-cadherin expression and down regulated expression of Vimentin,MMP1,MMP8,and other proteins.Conclusion Pantoprazole may exert therapeutic effects against IPF through multiple targets and signaling pathways.