Integrative multiomics and machine learning identify uridine as a candidate modulator of MMP7-mediated immune cell infiltration in pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD) characterized by immune cell infiltration and extracellular matrix (ECM) deposition. Effective therapies remain limited. Uridine is an endogenous nucleoside with pro-reparative and immunomodulatory effects, but its molecular targets and immune mechanisms in IPF remain unclear. OBJECTIVES: To identify potential uridine-associated targets in pulmonary fibrosis and to determine whether uridine is associated with matrix metalloproteinase 7 (MMP7)-related immune cell infiltration. METHODS: Uridine target predictions from multiple databases were integrated with bulk lung transcriptomes from three public ILD cohorts (n = 531). Machine learning with SHAP interpretation prioritized candidate targets. Molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR) evaluated uridine-protein interactions. Single-cell RNA-seq (∼540,000 cells) and spatial transcriptomics (19 IPF, 6 controls) mapped the cellular and spatial distribution of MMP7 and linked MMP7-enriched compartments to immune infiltration signatures. Key findings were validated in a bleomycin (BLM)-induced mouse model and in vitro assays. RESULTS: Integrative analyses prioritized five core genes (CA4, MME, MMP7, PTPRB, and TYMS; individual AUCs > 0.85), with MMP7 showing the highest SHAP importance. Higher MMP7 expression was associated with worse survival (HR = 2.93, p < 0.001). Single-cell and spatial analyses showed MMP7 enrichment in secretory epithelial cells, and MMP7-positive spot proportions correlated with histologic fibrosis severity (r = 0.807, p = 2.93 × 10-5). SPR confirmed direct uridine-MMP7 binding (KD = 6.73 × 10-6 M). In the BLM model, uridine attenuated fibrotic pathology and immune cell infiltration (total CD45+ cells: 777.8 vs. 3745 in BLM, p = 0.0002), accompanied by changes in MMP7, MIF, and MDK, consistent with modulation of immune microenvironment features. CONCLUSION: Integrative multiomics and machine learning analyses, together with in vitro and in vivo validation, suggest that uridine attenuates pulmonary fibrosis, potentially through modulation of MMP7-associated immune-microenvironment remodeling.