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

The chemical modification at the heart of the study is N6-methyladenosine, abbreviated m6A, the most abundant internal modification found in messenger RNA. In this process, a methyl group is attached to the nitrogen at position six of adenosine bases, a change that can alter how efficiently a transcript is translated, where it localizes, and, crucially, how long it survives before being degraded by the cell’s RNA-decay machinery. METTL3 is the catalytic core of the methyltransferase complex that writes these marks. Because m6A methylation has already been implicated in cancer, cardiovascular disease, and a range of fibrotic disorders, and because previous work showed that silencing METTL3 blocks the conversion of fibroblasts into scar-forming myofibroblasts, the team reasoned that the enzyme might also govern the lipid disturbances that increasingly appear central to pulmonary fibrosis.

That lipid connection is not incidental. Lipids serve not only as structural components of cellular membranes but also as signalling molecules that modulate fibroblast activation and extracellular matrix production, and dysregulated lipid metabolism has emerged as a critical factor in the pathogenesis of idiopathic pulmonary fibrosis. The protein PLIN2, a member of the perilipin family, coats the surface of intracellular lipid droplets and acts as a gatekeeper, controlling the entry of lipases and their cofactors into the stored lipids and thereby regulating lipolysis. PLIN2 has been linked to myocardial infarction, obesity, fatty liver disease, and lipogenic differentiation in lung fibrosis, but its relationship with METTL3 had never been explored.

To establish the disease context, the researchers used the well-characterized bleomycin model, in which the chemotherapy drug bleomycin is delivered directly into the airways of mice to provoke fibrotic injury that resembles the human condition. Histological examination with haematoxylin and eosin and Masson’s trichrome staining confirmed that bleomycin destroyed normal lung architecture and drove collagen deposition. Molecular assays showed elevated levels of the fibrosis markers collagen I and alpha-smooth muscle actin, while Nile Red fluorescence staining of lung sections revealed a marked increase in lipid deposition. Critically, METTL3 expression was significantly upregulated in the fibrotic lungs. The same pattern appeared in vitro: WI-38 human embryonic lung fibroblasts treated with transforming growth factor beta 1, a standard mimic of the fibrotic environment, also raised their METTL3 levels.

The team then asked what happens when METTL3 is removed. Using short hairpin RNA to knock down the enzyme in TGF-beta1-treated WI-38 cells, they observed a broad calming of the fibrotic program. Expression of lipogenesis markers including fatty acid synthase, acetyl-CoA carboxylase 1, SREBP1, and PPARalpha, all of which had been elevated by TGF-beta1, fell back toward baseline. Collagen I and alpha-smooth muscle actin declined at both the messenger RNA and protein levels, a result confirmed by immunofluorescence imaging of alpha-smooth muscle actin. Oil Red O staining showed that the abundance of lipid droplets induced by TGF-beta1 was partly abolished when METTL3 was silenced, demonstrating that the enzyme’s influence extends from scar formation to fat handling within the same cells.

The mechanistic core of the paper lies in what METTL3 does to PLIN2. When the researchers silenced METTL3, PLIN2 expression rose. Methylated RNA immunoprecipitation showed that the m6A levels on PLIN2 transcripts dropped in parallel, and RNA immunoprecipitation confirmed a direct physical interaction between METTL3 and the PLIN2 RNA. Using the SRAMP prediction database, the team identified five candidate methylation sites, selected the three with the highest confidence, and tested them individually with a dual-luciferase reporter assay in which the wild-type or site-mutated PLIN2 sequence was inserted downstream of a luciferase gene. Silencing METTL3 increased reporter activity only for the construct containing site 2, pinpointing that single adenosine as the functionally relevant methylation site. Actinomycin D chase experiments, which block new RNA synthesis and allow existing transcripts to decay, showed that METTL3 knockdown significantly prolonged PLIN2 messenger RNA half-life, confirming that the enzyme normally destabilizes the transcript through m6A-dependent decay.

To prove that PLIN2 is not merely a bystander but the functional downstream effector, the researchers performed an epistasis experiment. When they knocked down PLIN2 in cells in which METTL3 had already been silenced, the protective effects of METTL3 loss were reversed. The suppression of lipogenesis markers was abrogated, collagen I and alpha-smooth muscle actin climbed back up, and the reduction in lipid droplets was counteracted. In other words, removing PLIN2 restored the fibrotic and lipid-accumulating phenotype even in the absence of METTL3, placing PLIN2 squarely downstream of the methyltransferase in the pathway that connects RNA methylation to scar formation.

The in vivo experiments reinforced the story. Twenty mice per group were randomly assigned to control, bleomycin, bleomycin plus a control short hairpin RNA, or bleomycin plus shMETTL3 delivered intratracheally by adenovirus. Over 28 days, bleomycin reduced survival, while METTL3 knockdown improved it. Histology showed that silencing METTL3 impeded the destruction of lung structure and the deposition of collagen fibres. Nile Red staining demonstrated that the lipid accumulation driven by bleomycin was counteracted by METTL3 knockdown, and the elevated collagen I and alpha-smooth muscle actin levels in fibrotic lungs fell after METTL3 interference. Immunohistochemistry revealed that PLIN2, which was downregulated in the bleomycin model, was restored by METTL3 silencing, mirroring the cellular findings and tying improved survival and tissue architecture to the restored lipid-droplet protein.

The findings fit into a growing body of work implicating m6A machinery in fibrotic disease across organs. METTL3 knockdown has been reported to inhibit fibroblast proliferation and migration in cardiac fibrosis, to ameliorate kidney fibrosis by reducing fibrotic marker expression, and to promote macrophage pyroptosis that aggravates liver fibrosis. In the lung specifically, METTL3-mediated methylation has been shown to drive fibroblast differentiation into myofibroblasts through the miR-21/PTEN pathway, and m6A-modified circular RNAs have been linked to ferroptosis in pulmonary fibrosis. The new study extends this landscape by identifying PLIN2 as a novel methylation substrate and by connecting RNA epigenetics directly to lipid metabolism, a dimension of pulmonary fibrosis biology that involves lipofibroblast activation, lung remodelling, and pathways such as lysophosphatidic acid signalling.

The authors are careful to note the limitations of their work. WI-38 embryonic fibroblasts, while genetically stable and widely used to study the fibroblast-to-myofibroblast transition, cannot fully recapitulate the pathology of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis, and embryonic cells may differ from adult disease fibroblasts in epigenetic and lipid metabolic profiles, so validation in MRC-5 cells or primary patient fibroblasts will be needed. The team validated a single methylation site by reporter assay but did not perform transcriptome-wide m6A mapping such as MeRIP-seq or miCLIP to exclude additional sites, and the role of PLIN2 in vivo requires further preclinical testing. Even so, the central conclusion stands: METTL3 promotes lipid deposition and fibrosis by destabilizing PLIN2 messenger RNA in an m6A-dependent manner, and interventions that raise PLIN2 expression, whether directly or by silencing METTL3, offer a conceptually new route to treating a disease that urgently needs one.

Subject of Research: The role of METTL3-mediated m6A modification of PLIN2 in lipid metabolism and pulmonary fibrosis

Article Title: METTL3 Promotes Lipid Deposition and Pulmonary Fibrosis by Destabilizing PLIN2 in a m6A‐Dependent Manner

Article References: Liu, Q., Xu, R., & Du, X. (2026). METTL3 Promotes Lipid Deposition and Pulmonary Fibrosis by Destabilizing PLIN2 in a m6A‐Dependent Manner. Journal of Cellular and Molecular Medicine, 30(17), Article e71239. https://doi.org/10.1111/jcmm.71239

Image Credits: AI Generated

DOI: 10.1111/jcmm.71239

Keywords: idiopathic pulmonary fibrosis, METTL3, m6A methylation, PLIN2, lipid metabolism, RNA modification, pulmonary fibrosis, fibroblasts, myofibroblast, bleomycin model, epitranscriptomics, TGF-beta1