Identification of potential therapeutic targets for idiopathic pulmonary fibrosis: an integrated multiomics analysis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by persistent inflammation, aberrant extracellular matrix remodeling, and impaired tissue repair. Current antifibrotic drugs can slow disease progression but cannot reverse established fibrosis, highlighting the need to identify novel mechanism-based therapeutic targets.

We integrated batch-corrected transcriptomic data from the Gene Expression Omnibus with UK Biobank genome-wide association study statistics, including 1,369 cases and 435,866 controls, and proteomic GWAS instruments for plasma and cerebrospinal fluid proteins. Causal associations were evaluated using two-sample Mendelian randomization, Steiger filtering, reverse causality testing, and independent dataset validation. Expression-level validation was performed using bleomycin-induced mouse fibrosis and TGF-β1-stimulated fibroblast models.

Twelve proteins were identified as being associated with IPF risk, including eight pro-fibrotic mediators, such as FN1, CCL5, PPID, and CDON, and four protective factors, including SCARF2, IL7R, ESAM, and CD274. Multi-omics integration and experimental validation prioritized four candidate proteins: SCARF2 as a protective factor, and FN1, PPID, and CDON as pro-fibrotic factors. Network analysis linked FN1 to extracellular matrix remodeling and SCARF2 to scavenger receptor-mediated immune regulation, indicating distinct fibrotic and immunomodulatory pathways.

These findings identify several potential therapeutic targets for IPF and provide a translational framework for developing disease-modifying therapies that may overcome the limitations of current antifibrotic treatments.