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Integrative multiomics and machine learning identify uridine as a candidate modulator of MMP7-mediated immune cell
Wanda Bi1, Ying Zhou2, Junhui Gong3
1State Key Laboratory of Trauma and Chemical Poisoning, Department of Trauma Medical Center, Daping Hospital, Army Medical University, Changjiang Branch Road 10, Daping Street, Yuzhong District, Chongqing 400042, China; Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing 400042, China.
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.