The study, led by Wanda Bi, Jianxin Jiang, Saiying Hou and Li Li, combined an unusually broad arsenal of approaches: patient transcriptomic datasets, a machine-learning pipeline spanning twelve algorithms, single-cell and spatial transcriptomics, molecular docking simulations, and classical animal and cell experiments. The researchers began by treating mice in which pulmonary fibrosis had been induced with bleomycin, a chemotherapy drug that reliably scars the lungs. Starting one day after injury, the animals received intraperitoneal injections of uridine every 48 hours for three weeks. The results were striking. Survival at day 21 rose from 40 percent in untreated fibrotic mice to 84.6 percent in those given the higher, 4 mg/mL dose of uridine. Body weight recovered, lung architecture was better preserved, and collagen deposition—the hallmark of fibrosis—fell dramatically, with the collagen volume fraction dropping from 47.79 percent to 12.22 percent of tissue area.

Crucially, the treatment appeared safe. Serum biochemistry measuring kidney and liver function, along with histological examination of the kidney, liver, spleen, heart and lung, revealed no detectable toxicity. That safety profile matters because uridine is an endogenous molecule, already present in the body as a central player in pyrimidine metabolism and RNA biosynthesis, and prior work has suggested it carries regenerative and anti-inflammatory properties across multiple organs. But knowing that a molecule helps is not the same as knowing how, and this is where the study’s computational machinery came into play.

The team mined a public dataset of interstitial lung disease transcriptomes, corrected for batch effects, and identified more than a thousand genes altered in diseased lungs. Weighted gene coexpression network analysis then grouped these genes into modules correlated with clinical traits such as lung diffusion capacity and disease status. In parallel, three pharmacology databases—ChEMBL, SwissTargetPrediction and PharmMapper—were used to predict which human proteins uridine might physically engage. Intersecting the two lists yielded 28 candidate targets, and a machine-learning framework that cross-combined feature-selection and classification algorithms into 128 distinct models whittled the field down to five core genes: MMP7, CA4, MME, PTPRB and TYMS. Each of these individually distinguished patients from healthy controls with an area under the curve above 0.85, and a diagnostic nomogram built from all five achieved an AUC of 0.925 in validation cohorts.

MMP7 stood out. Interpretability analysis using SHAP values ranked it as the most influential predictor in the model, and its expression correlated strongly with clinical reality: the more MMP7 a patient expressed, the worse their diffusing capacity for carbon monoxide, and patients with high MMP7 in bronchoalveolar fluid survived significantly less long, with a hazard ratio of 2.93. Single-cell RNA sequencing of more than half a million cells from 127 human lung samples localized the signal with precision. MMP7 was highly expressed in basal and secretory epithelial cells, and its expression in secretory cells climbed steadily as fibrosis advanced from limited to severe. Spatial transcriptomics of human lung tissue reinforced the picture, showing that the proportion of MMP7-positive spots correlated tightly with histologic fibrosis scores, and that MMP7-rich hotspots colocalized with regions of dense immune infiltration, particularly macrophages, monocytes and neutrophils.

That spatial coupling between MMP7 and immune cells is the conceptual heart of the paper. MMP7 has long been regarded mainly as a biomarker of extracellular matrix degradation in IPF, but the new data suggest it may do something more active: reshape the immune microenvironment. Cell-cell communication analysis using CellChat showed that, in fibrotic lungs, secretory cells dramatically increase their signaling with dendritic cells, B cells, macrophages and T cells, activating pathways involved in antigen presentation, integrin-mediated adhesion and cytotoxic T-cell responses. In the bleomycin model, MMP7-positive secretory cells sat in close proximity to CD45-positive immune cells, F4/80-positive macrophages and Ly6G-positive neutrophils, and these populations expanded dramatically after injury.

Could uridine directly engage MMP7? The team built the case at the molecular level. Molecular docking predicted a favorable binding energy of −6.5 kcal/mol between uridine and MMP7, and a 100-nanosecond molecular dynamics simulation showed a stable complex with persistent hydrogen bonds and the residue GLU219 emerging as an energetic hotspot. Surface plasmon resonance on a Biacore system then confirmed concentration-dependent binding between uridine and recombinant human MMP7, with an equilibrium dissociation constant of 6.73 micromolar. A biotin-labeled uridine pull-down assay in human bronchial epithelial cells enriched MMP7, and free uridine competed that signal away—three independent lines of evidence for a physical interaction.

Functional experiments then connected the dots. In BEAS-2b airway epithelial cells, bleomycin raised MMP7 protein levels, and uridine brought them back down. When the researchers knocked down MMP7 with siRNA, the pro-inflammatory cytokine macrophage migration inhibitory factor, or MIF, fell while midkine, or MDK—a molecule associated with tissue repair—rose. Uridine produced the same directional shift, and adding recombinant MMP7 back into the cultures partially reversed uridine’s effects on MIF and antigen-presentation genes. The authors are careful to frame this as a hypothesis-generating mechanism rather than a fully resolved causal chain, but the pattern was consistent: MMP7 appears to bias the epithelial niche toward inflammatory signaling, and uridine seems to tip it back toward repair. In living mice, uridine treatment cut the total immune cell population in bronchoalveolar lavage fluid by roughly 80 percent, with significant reductions in neutrophils, macrophages and T cells, while messenger RNA levels of IL-1β, IL-6 and TGF-β1 all dropped. Bulk RNA sequencing of treated lungs confirmed dampened inflammatory, innate immune and adaptive immune signatures, and Mmp7 expression positively tracked with neutrophil and macrophage infiltration scores.

The translational implications are intriguing but guarded. Broad-spectrum matrix metalloproteinase inhibitors have historically stumbled over toxicity, which makes the idea of modulating a single MMP through an endogenous, well-tolerated metabolite attractive. Because MMP7 is also implicated in kidney fibrosis, the approach could theoretically extend beyond the lung. Yet substantial hurdles remain. Circulating uridine is rapidly degraded in the liver by uridine phosphorylase, severely limiting oral bioavailability, which is why the team chose injection; whether effective pulmonary exposure can be achieved clinically, and by which route, is unknown. The study used an early intervention window, whereas patients typically present with established disease, and the authors themselves note that definitive proof will require epithelial-specific MMP7 knockout models, humanized systems such as precision-cut lung slices from IPF patients, and careful dose-ranging work. Some discrepancies—such as divergent PTPRB patterns between mice and humans, and an unexplained rise in B cells despite MMP7 suppression—underscore that parallel pathways are at play.

Even with those caveats, the convergence of evidence is what makes the paper notable. A candidate molecule emerged not from a single screen but from multiple independent analytical layers—coexpression networks, machine learning, single-cell atlases, spatial maps, structural simulations and wet-lab validation—all pointing at the same node. If future work confirms that uridine, or derivatives engineered to survive first-pass metabolism, can safely suppress MMP7-high epithelial programs in human lungs, it could open a genuinely new front against a disease that has stubbornly resisted them. For now, the study offers something IPF research has badly needed: a testable, mechanistically grounded hypothesis linking metabolism, epithelial injury and immune remodeling in the fibrotic lung.

Subject of Research: Uridine as a candidate modulator of MMP7-mediated immune cell infiltration in pulmonary fibrosis

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

Article References: Bi, W., Zhou, Y., Gong, J., Liu, W., Li, J., Du, J., Nie, H., Luo, H., Zhang, H., Cai, Q., Gao, C., Zeng, L., Jiang, J., Hou, S., & Li, L. (2026). Integrative multiomics and machine learning identify uridine as a candidate modulator of MMP7-mediated immune cell infiltration in pulmonary fibrosis. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.008

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.008

Keywords: pulmonary fibrosis, idiopathic pulmonary fibrosis, uridine, MMP7, multiomics, machine learning, single-cell RNA sequencing, spatial transcriptomics, immune cell infiltration, molecular docking, bleomycin model, antifibrotic therapy