Abstract
BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease with scarce therapeutic alternatives, which imposes a significant economic burden on society. The identification of novel drug targets is thus critically essential. Plasma proteins with discernible causal evidence hold promise as viable drug targets for this condition. METHODS: We performed a proteome-wide Mendelian randomization (MR) analysis to assess the causal effects of 4,907 circulating proteins from the deCODE study on the risk of IPF from the Finngen Database (2,018 cases vs. 373,064 controls). We further replicated the MR analysis in 1426 proteins from the ARIC study and IPF from the UK Biobank (1,369 cases vs. 435,866 controls). Then a series of analyses including Bayesian colocalization, Steiger filtering, and phenotype scanning were conducted to validate the credibility of the MR results. Subsequently, protein-protein interaction (PPI) analysis, pathway enrichment analysis, and druggability assessment were executed to elucidate the underlying mechanisms. Finally, the findings were corroborated using a bleomycin-induced pulmonary fibrosis mouse model. RESULTS: The MR analysis bolstered by robust evidence of colocalization, indicated a significant positive association between Prothrombin and increased IPF risk (OR = 3.26,95%CI 1.75-6.07). Conversely, Bone Sialoprotein (IBSP) demonstrated an inverse association with IPF susceptibility (OR = 0.27,95%CI 0.14-0.55). CONCLUSIONS: The integrative analysis suggests that Prothrombin and IBSP are promising candidates as potential drug targets for IPF. Additional clinical investigations are warranted to substantiate these findings.