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However, the exact mechanism of action and clinical efficacy require further investigation and validation. This study commenced by identifying pathogenic genes associated with IPF through the GeneCards database. Potential targets of pirfenidone were subsequently screened through PubChem and Swiss TargetPrediction, and overlapping targets were identified through Venn diagram analysis. Enrichment analysis of potential target genes was performed to identify the key biological processes and pathways involved in the action of pirfenidone. The main target genes were subsequently identified through the GSE10667 and GSE110147 datasets. The affinity of PDE1A to pirfenidone was predicted by molecular docking and MicroScale Thermophoresis (MST). Finally, the expression and antifibrotic effects of pirfenidone on PDE1A were validated through data from the GSE226249 dataset. PDE1A, identified by GeneCards and Swiss TargetPrediction, was found to be an important mediator of the antifibrotic effect of pirfenidone. The enrichment analysis revealed biological processes such as cyclic nucleotide-mediated signaling and cAMP-mediated signaling. KEGG pathway analysis further linked pirfenidone activity to pathways involved in calcium signaling, taste transduction, morphine dependence, renin secretion and purine metabolism. Molecular docking, molecular dynamics (MD) simulations and MST results revealed a strong binding affinity between pirfenidone and PDE1A. MD simulations showed the stability of the complex. It was observed that the RMSD analysis of the complex stabilized between 0.6 to 0.8 nm throughout the simulation, however RMSF showed minimal fluctuation. Data from the GSE226249 dataset confirmed that upregulation of PDE1A promotes fibrosis, whereas pirfenidone downregulates PDE1A, thereby exerting its antifibrotic effect. The inhibition of IPF progression by pirfenidone is mediated by PDE1A, providing insights into its therapeutic mechanism.<\/jats:p>","DOI":"10.1371\/journal.pone.0342991","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:39:21Z","timestamp":1775842761000},"page":"e0342991","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Network pharmacology and integrative bioinformatics analyses identify PDE1A as a key target of pirfenidone in idiopathic pulmonary 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