Assessing the Causal Relationship Between Plasma Proteins and Pulmonary Fibrosis: A Systematic Analysis Based on Mendelian Randomization.

Abstract

Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by the destruction of alveolar structures, the abnormal accumulation of extracellular matrix (ECM), and ultimately respiratory failure. Although previous studies have shown that plasma proteins play an important role in the onset and progression of PF, there is currently a lack of systematic studies on causal relationships. To address the identified gap, the study employs the MR method to identify potential drug targets associated with PF. Plasma protein data (pQTL, exposure) were sourced from Ferkingstad et al. (n = 35,559), and PF-related summary statistics were obtained from the GWAS database (n = 469,126). The study integrates enrichment analysis, protein-protein interaction (PPI) networks, drug prediction, molecular docking, and single-cell sequencing to further evaluate the biological functions and pharmacological potential of the identified targets. In the MR analysis, 64 genetic loci were significantly associated with the occurrence of PF. Further reverse Mendelian analysis revealed a positive causal relationship between PF and genes such as NPTX1, IL31, and CTSE, suggesting that these proteins may play a promotive role in the onset and progression of pulmonary fibrosis. The PPI network analysis identified core genes such as CDH1, CRP, VTN, COL1A1, and MAPK8, which are involved in the key pathological processes of PF, including cell signaling, ECM remodeling, and immune responses. The drug prediction analysis identified potential drugs such as sorafenib, vitamin C, and vitamin E, and the molecular docking analysis showed good binding between the drugs and the proteins. The single-cell sequencing results showed that core genes were highly expressed in fibroblasts and alveolar type II cells, confirming their potential role in the pathogenesis of PF. This study successfully identifies 64 potential drug targets for PF, with 10 core targets considered particularly promising for clinical trials. These findings offer valuable insights into the molecular mechanisms underlying PF and open new avenues for the development of targeted therapies. This research may accelerate the development of effective PF treatments and reduce drug development costs by providing more precise and personalized approaches to managing the disease.