The Role of Age-Related Genes in Idiopathic Pulmonary Fibrosis and Molecular Docking Analysis of Their Drug Targets

Wei Zhang¹Tingting Xia^2*QIAN ZHANG^3*

• ¹Affiliated Hospital of Zunyi Medical University, Zunyi, China
• ²The Tenth Affiliated Hospital of Southern Medical University, Dongguan, China
• ³The First People's Hospital of Zunyi, Zunyi, China

Background: Idiopathic pulmonary fibrosis (IPF), a relentlessly progressive lung 23 disorder marked by unremitting extracellular matrix deposition, continues to 24 challenge clinical management due to its enigmatic etiology. Emerging evidence 25 positions biological aging as a critical orchestrator of fibrotic reprogramming, where 26 senescent cell accumulation and dysregulated tissue repair converge to drive disease 27 progression. 28 Methods: Three independent IPF transcriptomic datasets (GSE24206, GSE53845, 29 GSE68039) were retrieved from the Gene Expression Omnibus (GEO) database. 30 Aging-related differentially expressed genes (DEGs) were identified through 31 intersection analysis with established senescence-associated gene sets. Functional 32 annotation was performed using Gene Ontology (GO) and Kyoto Encyclopedia of 33 Genes and Genomes (KEGG) pathway analyses. Protein-protein interaction (PPI) 34 networks were constructed via STRING database and visualized using Cytoscape to 35 identify topological hub genes. Competing endogenous RNA (ceRNA) networks and 36 transcription factor (TF)-gene regulatory relationships were subsequently established. 37 The DSigDB database was employed for drug-gene interaction prediction, 38 complemented by molecular docking validation. Experimental validation was 39 conducted using the GSE10667 dataset and a bleomycin-induced murine pulmonary 40 fibrosis mode. 41 Results: Comparative transcriptomic analysis revealed 292 DEGs between IPF and 42 control tissues, with 19 exhibiting significant aging-related characteristics. Network 43 topology analysis identified ten hub genes, including CLU and LCN2, that occupied 44 central positions in both ceRNA networks and TF regulatory circuits. Drug 45 enrichment analysis nominated inulin and meclizine as promising candidates 46 demonstrating stable binding conformations with LCN2 and CLU, respectively. 47 External validation confirmed significant upregulation of CLU and LCN2 in 48 GSE10667 dataset, consistent with murine model findings. 49 To bridge the knowledge gap between aging hallmarks and IPF pathobiology, this study integrates multi-omics profiling with computational pharmacology to decipher senescence-associated molecular networks and their therapeutic vulnerabilities. 删除[巍]: 3 Conclusion: Our integrative analysis reveals novel molecular connections between 50 cellular senescence programs and fibrotic lung remodeling, positioning 51 CLU and LCN2 as pivotal regulators of age-associated pulmonary fibrosis. The 52 identified drug candidates exhibit therapeutic potential through multi-target 53 engagement mechanisms, providing a translational framework for developing 54 senescence-modulating therapies in IPF.