Exploration of Potential Therapeutic Targets of Diosgenin in Pulmonary Fibrosis through Network Pharmacology and Mendelian Randomization

Background: Pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF), is a chronic, progressive lung disease with limited therapeutic options. Diosgenin, a steroidal sapogenin, has been suggested to have potential therapeutic effects on various diseases. This study aims to identify and validate potential protein targets of diosgenin in pulmonary fibrosis using comprehensive bioinformatics analysis and Mendelian randomization. Methods: The potential targets of diosgenin were initially identified through SwissTargetPrediction and Super-PRED databases, resulting in 234 predicted protein targets. Pathway analysis and the construction of a protein-protein interaction (PPI) network were performed to elucidate the functional pathways of these targets. Subsequently, we intersected these targets with genes associated with pulmonary fibrosis to identify core targets. Mendelian randomization (MR) for pulmonary fibrosis and idiopathic pulmonary fibrosis was conducted using five different MR methods. Results: 14 core targets were fetched through our analysis, including STAT3, BRAF, CFTR, DPP9, ICAM1, IL2, MMP1, NFKB1, NOS2, NOS3, PDGFRA, SERPINE1, SRC, and TLR4. Among the 14 core targets, Intercellular Adhesion Molecule 1 (ICAM1) and Nuclear Factor Kappa B Subunit 1 (NFKB1) both showed significant associations with postinflammatory pulmonary fibrosis. Specifically, ICAM1 was associated with an increased risk of postinflammatory pulmonary fibrosis (OR [95% CI] = 2.07 [1.16–3.68], P = 0.014), while NFKB1 was similarly associated with an increased risk (OR [95% CI] = 2.25 [1.13–4.49], P = 0.022). These findings indicate potential causal relationships between these genes and the development of postinflammatory pulmonary fibrosis. Conclusion: This study identifies Intercellular Adhesion Molecule 1 (ICAM1) and Nuclear Factor Kappa B Subunit 1 (NFKB1) as significant genetic associations with postinflammatory pulmonary fibrosis, suggesting their potential roles as therapeutic targets. The findings indicate that both ICAM1 and NFKB1 may contribute to the pathogenesis of postinflammatory pulmonary fibrosis, providing a foundation for further experimental validation and therapeutic exploration aimed at these targets.