J Nutr. 2025 Jul 1:S0022-3166(25)00413-4. doi: 10.1016/j.tjnut.2025.06.024. Online ahead of print.

ABSTRACT

BACKGROUND: The association between calcium supplementation and the risk of incident idiopathic pulmonary fibrosis (IPF) is largely unknown.

OBJECTIVES: This study aimed to investigate the association of calcium supplementation with IPF incidence, and further explore the modification effect of genetic susceptibility.

METHODS: This study analyzed 472,468 participants from the UK Biobank. The information on the calcium supplement use was obtained from baseline touch-screen questionnaire and IPF case was identified using the International Classification of Diseases with the 10th edition (ICD-10) codes J48.1 and further excluded secondary pulmonary fibrosis-related diseases. We used the Cox proportional hazard model to assess the association between calcium supplementation and the risk of IPF incidence. Besides, we calculated IPF-specific polygenic risk score (PRS) for each individual and assessed the modification effect of genetic susceptibility.

RESULTS: During a median follow-up of 12.82 years, a total of 1859 new-onset IPF cases were identified. After adjusting traditional risk factors, we found that calcium supplement use was significantly associated with a 30% increased risk of IPF (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.08-1.57). Stratified analyses showed that sex modified the observed associations, and the adverse effect of calcium supplement use were stronger among males (P interaction: 0.037). Moreover, there was a cumulative effect of genetic factors and calcium supplementation on the risk of incident IPF. Compared with calcium supplementation non-users with low genetic risk, those with calcium supplementation and high genetic risk had the highest risk of IPF incidence (HR: 3.47, 95% CI: 2.59-4.66).

CONCLUSIONS: This study provides observational evidence that calcium supplementation may be a novel risk factor for IPF. Our findings highlight the importance of caution regarding the use of calcium supplements. Further experimental studies are still required to validate our results and elucidate the exact mechanisms.

PMID:40609689 | DOI:10.1016/j.tjnut.2025.06.024

Front Immunol. 2025 Jun 18;16:1609509. doi: 10.3389/fimmu.2025.1609509. eCollection 2025.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and irreversible lung damage. A key driver of disease progression is the phenotypic shift of lipofibroblasts (LIFs) into activated myofibroblasts (aMYFs), triggered by sustained epithelial injury, caused by inflammation, oxidative stress, viral infections (e.g., influenza, SARS-CoV-2), and metabolic dysfunction. Emerging evidence demonstrates that this transition is reversible, with pharmacological agents that promote aMYF-to-LIF reprogramming contributing to fibrosis resolution. The identification of inflammatory lipofibroblasts (iLIFs) highlights the importance of inflammation in fibrosis progression. Inflammation, mediated by IL-1β, IL-17A, and TGF- β, sustain aMYF activation, while immune cells shape fibrosis formation. This review combines current insights on the cellular and molecular pathways controlling fibroblast differentiation, highlighting key metabolic, immunologic, and oxidative stress-modulating targets for therapeutic intervention. Understanding and manipulating the LIF-iLIF-aMYF axis offers a promising strategy for reversing fibrosis and restoring pulmonary homeostasis in IPF.

PMID:40607394 | PMC:PMC12213413 | DOI:10.3389/fimmu.2025.1609509

Front Genet. 2025 Jun 18;16:1602588. doi: 10.3389/fgene.2025.1602588. eCollection 2025.

ABSTRACT

INTRODUCTION: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disorder characterized by excessive fibrosis and structural remodeling of lung tissue. The role of inflammation in developing and progressing IPF is increasingly recognized as critical. However, the precise mechanisms and pathways of inflammation in IPF remain unclear. This study aimed to identify inflammation-related genes in IPF and develop a prognostic risk model using machine learning approaches.

METHODS: The IPF dataset GSE70866 from the Gene Expression Omnibus database was analyzed to identify inflammation-related genes. Unsupervised clustering algorithms were used to classify IPF samples, followed by weighted gene co-expression network analysis (WGCNA) to identify highly correlated genes. Least absolute shrinkage and selection operator (LASSO) regression was then applied, and the intersection of results pinpointed critical hub genes, primarily CCL2 and STAB1. A rat model of pulmonary fibrosis was established, and lentivirus transfection was used to knock down CCL2 expression. The transfection effect and hub gene expression were validated using Quantitative polymerase chain reaction, Western blot, immunohistochemistry, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, and Masson's trichrome staining. Levels of α-SMA and COL1A1 were also assessed.

RESULTS: WGCNA and LASSO regression analyses identified CCL2 and STAB1 as significant contributors to IPF, closely associated with patient prognosis and immune cell infiltration. Protein-protein interaction network analysis established CCL2 as a novel biomarker for IPF. In a rat model of IPF, CCL2 expression was significantly elevated compared to that in the controls. Knockdown of CCL2 expression alleviated pulmonary fibrosis and reduced the expression of COL1A1 protein and α-SMA protein. CCL2 promotes the expression of COL1A1 protein and α-SMA proteins, suggesting that the mechanism of inflammation-induced pulmonary fibrosis may involve the regulation of COL1A1 and α-SMA by CCL2.

DISCUSSION: These findings establish CCL2 as a promising biomarker and potential therapeutic target for IPF.

PMID:40606673 | PMC:PMC12213808 | DOI:10.3389/fgene.2025.1602588

Front Med (Lausanne). 2025 Jun 18;12:1534903. doi: 10.3389/fmed.2025.1534903. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive pulmonary disorder marked by the gradual substitution of lung tissue with fibrotic tissue, resulting in respiratory failure. While the precise etiology of IPF remains unclear, an increasing number of studies have indicated that programmed cell death (PCD) significantly contributes to the onset and advancement of IPF. PCD is implicated not only in the impairment of alveolar epithelial cells during fibrosis but also in the alterations of immune cells inside the fibrotic milieu. Investigating the PCD patterns offers a novel approach to the early diagnosis and prognostic evaluation of IPF.

METHODS: The study utilized microarray-based transcriptome profiling and single-nucleus RNA sequencing to identify and analyze diverse PCD patterns in IPF. IPF-related genes were identified based on differential expression analysis, univariate Cox regression analysis, the "Scissor" program, and the "Findmarkers" program. A combination of machine learning was employed to develop stable predictive and diagnostic signatures associated with IPF, based on the filtered relevant genes.

RESULTS: The stable PCDI.prog signature was established through the integration of 101 distinct machine-learning techniques, which exhibited superior efficacy in predicting outcomes in IPF patients through the validation of multiple datasets. Integrating PCDI.prog signature with patient clinical information, such as age, gender, and GAP score, enables the prediction of disease progression rates and patient survival. Additional PCDI.diag signature can offer insights into the early diagnosis of IPF.

CONCLUSION: In summary, PCDI.prog signature and PCDI.diag signature offer critical insights for the early diagnosis, prognostic evaluation, and personalized treatment of IPF.

PMID:40606472 | PMC:PMC12216088 | DOI:10.3389/fmed.2025.1534903

J Leukoc Biol. 2025 Jul 3:qiaf100. doi: 10.1093/jleuko/qiaf100. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive incurable lung disease characterized by chronic inflammation and fibrosis, with innate immune cells such as neutrophils and macrophages playing central roles in its pathogenesis. This review explores the involvement of these immune cells in the inflammatory process of IPF, focusing on their contribution to disrupted tissue repair and impaired resolution. The balance between host defense mechanisms, including leukocyte recruitment, and the release of pro-resolving mediators is crucial for maintaining healthy tissue function and returning to pre-inflammatory states. We highlight the importance of inflammation resolution to prevent an overactive immune response, which can lead to irreversible fibrosis. Specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins, are discussed in terms of their regulatory effects on neutrophils and macrophages in IPF. These mediators exhibit potent anti-inflammatory actions, which can modulate the immune response and promote the resolution of inflammation. Overall, this review underscores the significance of immune modulation in IPF, with a focus on the therapeutic potential of SPMs in controlling the inflammatory response and preventing fibrosis progression. Future research into the anti-fibrotic properties of SPMs and their impact on innate immune cell regulation holds promise for novel therapeutic strategies in IPF treatment.

PMID:40605609 | DOI:10.1093/jleuko/qiaf100

Eur J Med Res. 2025 Jul 2;30(1):542. doi: 10.1186/s40001-025-02755-5.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an unexplained interstitial lung disease in which senescence is a central risk factor. Senescent cells drive chronic inflammation and fibrosis by the secreting senescence-associated secretory phenotype (SASP). Interleukin-11 (IL-11), a core factor in the SASP, is significantly upregulated in IPF lung tissues.IL-11 promotes lung cellular senescence and chronic inflammation through the activation of the JAK2/STAT3 and MEK/ERK1/2 pathways. It also leads to extracellular matrix protein deposition by promoting fibroblast-myofibroblast transformation, epithelial mesenchymal transition and endothelial mesenchymal transition. Targeting IL-11 has antiaging and fibrotic effects. Nanoparticle delivery therapeutic regimens targeting IL-11 show potential in animal models of IPF, but evidence for their clinical application is lacking. Future studies should focus on the dynamic molecular regulatory mechanisms of IL-11 in IPF, as well as the development of targeted delivery systems and multitarget combined intervention therapeutic regimens. This review systematically analyzes the molecular mechanisms of IL-11 in IPF and provides new perspectives for the treatment of aging-associated pulmonary fibrosis.

PMID:40605040 | DOI:10.1186/s40001-025-02755-5

Respir Res. 2025 Jul 2;26(1):228. doi: 10.1186/s12931-025-03304-8.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a highly variable clinical course. Forced vital capacity (FVC) is widely used as a marker of disease severity and progression, yet its variability and dependence on patient effort raise concerns regarding its reliability. Given these limitations, we investigated the clinical significance of slow vital capacity (SVC) as a potential alternative measure of lung function in IPF.In a retrospective cohort of 89 IPF patients who underwent pulmonary function testing with concomitant SVC measurements, we observed a strong correlation between FVC and SVC (r = 0.973 at baseline, r = 0.978 at follow-up). However, in 99% of cases, SVC values were equal to or exceeded FVC, and follow-up assessments revealed that FVC exhibited greater variability than SVC. Notably, patients with a decrease in SVC demonstrated worse survival outcomes, whereas FVC decline did not show the same prognostic significance. These findings suggest that SVC may provide a more stable and clinically meaningful measure of disease progression in IPF. Moreover, its less effort-dependent nature could improve reproducibility, particularly in patients with advanced diseases.Our study highlights the potential role of SVC as a valuable metric in clinical practice and as an endpoint in future IPF trials. Prospective validation of these findings could further establish SVC as a superior tool for disease monitoring and therapeutic assessment.

PMID:40605031 | DOI:10.1186/s12931-025-03304-8

Respir Res. 2025 Jul 2;26(1):221. doi: 10.1186/s12931-025-03306-6.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and fatal disease with few effective therapies available. Fibrosis is driven, in part, by cell-state transitions of epithelial progenitors within the airways that repopulate the injured alveoli. This alveolar atypia affects gas exchange and stimulates ECM production. We sought to examine the role of BRD4 signaling in progenitor expansion in bleomycin-induced lung injury.

METHODS: Activation of the Bromodomain-containing protein 4 (BRD4) epigenetic regulator in distinct stem cell populations was quantitated in a high-resolution scRNA-seq time course of bleomycin-induced injury, and confirmed in scRNA-seq studies in human IPF. A potent, selective, and orally bioavailable BRD4 inhibitor (BRD4i, ZL0969) was rationally designed and synthesized. The effect of BRD4i on myofibroblast transition, progenitor cell expansion and fibrosis was evaluated using a therapeutic experimental design in C57BL6/mice.

RESULTS: We find that the BRD4 pathway is rapidly induced in regenerating activated alveolar type (AT)2 cells and persists in a population of pro-fibrotic Krt8 + progenitors expressing markers of epithelial mesenchymal transition as well as senescence. To test the functional role of BRD4 activation, we administered a potent, selective, and orally bioavailable BRD4 inhibitor (BRD4i, ZL0969) with ~ 80 nM IC50 to bleomycin-treated mice. BRD4i reduced myofibroblast formation and deposition of denatured ECM (collagen and laminin a1) in the alveolar space and improved disease scores. Importantly, BRD4i reduced a pathogenic population of alveolar progenitor cells expressing integrin (ITG)-A6/B4, tumor related protein 63 (Trp63) and keratin (Krt). In mice given an LD50 dose of bleomycin, BRD4 inhibition significantly improved their survival and reduced markers of disease.

CONCLUSIONS: These data demonstrate that inhibition of BRD4 signaling prevents expansion of myofibroblasts and expansion of a pathogenic epithelial progenitor population controlling alveolar atypia and fibrosis.

PMID:40604997 | DOI:10.1186/s12931-025-03306-6

Respir Res. 2025 Jul 2;26(1):230. doi: 10.1186/s12931-025-03294-7.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with chronic progressive fibrosis of unknown etiology; it is characterized by persistent fibrosis of the lungs accompanied by irreversible lung function decline and high mortality rates. A large body of evidence suggests a significant association between IPF and lung cancer (LC). IPF itself increases the risk of LC development, and LC associated with IPF often originates in areas of honeycomb lesions in IPF. In addition, there are similarities between the two diseases in terms of genetics as well as cellular molecular mechanisms; examples include genetic and epigenetic variants, fibroblast activation and proliferation, epithelial‒mesenchymal transition (EMT), abnormal mechanical forces generated in the lungs, and aberrant signaling pathway activation, which may drive the progression of pathology in both diseases. In this review, we describe in detail the epidemiological and clinical associations of LC in patients with IPF, highlight recent studies on the shared pathogenesis between IPF and LC, and discuss current advances in the treatment of LC associated with idiopathic pulmonary fibrosis.

PMID:40604973 | DOI:10.1186/s12931-025-03294-7

Respir Res. 2025 Jul 2;26(1):225. doi: 10.1186/s12931-025-03300-y.

ABSTRACT

BACKGROUND: Transcriptome profiling by RNA sequencing (RNAseq) can provide insightful information on the molecular processes underlying disease development and progression. Although fresh tissue represents the preferred source material for RNAseq, here, we investigated the feasibility of applying RNAseq analysis to single 10 μm thick formalin-fixed and paraffin-embedded (FFPE) lung slides from the lungs of control and bleomycin (BLM)-treated mice. This approach aims at providing spatial-oriented transcriptomic data, that can be integrated with in vivo and ex vivo readouts obtained on the same sample, as a way to enhance the mechanistic information and biomarker/target discovery potential of preclinical models of fibrotic lung diseases.

METHODS: RNAseq analysis was conducted on individual FFPE slides from the lungs of both controls and BLM-treated mice. The results were initially validated by comparison with publicly available bulk data from fresh-frozen (FF) mouse tissues, both untreated and BLM-treated, as well as human idiopathic pulmonary fibrosis (IPF) biopsies. Unsupervised cluster analysis was performed on Differentially Expressed Genes (DEGs) distinguishing untreated and BLM-treated fibrotic lung samples. For each sample, Pearson correlation analysis was used to compare expression levels of individual gene clusters with Ashcroft Scores and aeration compartments quantitatively assessed on the matched 2D micro-CT coronal slice.

RESULTS: Over 90% of annotated genes within the FFPE dataset were shared with gene signatures retrieved from FF bulk datasets. Differentially modulated gene clusters were mainly found to be associated with extracellular matrix (ECM) organization, tissue remodeling, and inflammatory response pathways. For each sample, expression levels of individual gene clusters were highly correlated with 2D histology readouts and aeration compartments determined on matched 2D coronal slices by micro-CT imaging.

CONCLUSIONS: FFPE lung tissue represents a valuable alternative to fresh tissue for RNAseq analysis, allowing to achieve a more precise, spatially oriented picture of pulmonary disease development. This approach is thus instrumental to a better characterization of the molecular changes associated to each sample. It can also contribute to a more informed interpretation of histology and micro-CT imaging data, paving the way to the identification of translationally relevant biomarkers as well as novel candidate targets for the development of more effective therapeutic interventions.

PMID:40604969 | DOI:10.1186/s12931-025-03300-y

BMC Pulm Med. 2025 Jul 2;25(1):295. doi: 10.1186/s12890-025-03696-9.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare, progressive, and fibrotic disease with poor prognosis that lacks treatment options. As a major component of the lung adaptive immune system, plasma cells play a crucial regulatory role during fibrosis. The aim of this study is to systematically explore plasma cells-related genes associated with prognosis in patients with IPF.

METHODS: The marker genes for plasma cells were extracted via single-cell RNA sequencing (scRNA-seq) analysis. Hub genes most relevant to the IPF state and plasma cells infiltration level were screened by weighted gene co-expression network analysis (WGCNA). Moreover, the differentially expressed genes (DEGs) were obtained based on the bulk RNA-seq and microarray data. In addition, a machine learning-based integrative procedure for constructing a concordance plasma cells-related gene signature (PCRGS) was developed. A core gene in the PCRGS was further identified and validated through experiments. Finally, the network pharmacology analysis for the core gene was implemented.

RESULTS: The established PCRGS, based on the seven genes (SLAMF7, JCHAIN, PNOC, POU2AF1, MEI1, ST6GAL1, and VOPP1), was identified as an independent prognostic factor for overall survival. It also demonstrated well robustness compared to conventional clinical features and 22 published signatures. Eventually, ST6GAL1 was selected as the core gene and its localization in the plasma cells as well as its over-expression in the lungs of bleomycin-injured mice was experimentally validated. The small molecular drugs prediction and docking analysis suggest quercetin as the optimal ligand targeting ST6GAL1 which might form a stable binding conformation with it.

CONCLUSIONS: PCRGS might be used to evaluate the IPF prognosis, among which ST6GAL1 is a potential therapeutic target. These results provide an important basis for future studies on the relationship between plasma cells-related genes and IPF.

PMID:40604645 | DOI:10.1186/s12890-025-03696-9

Sci Rep. 2025 Jul 1;15(1):21580. doi: 10.1038/s41598-025-08969-1.

ABSTRACT

Fibrotic interstitial lung disease (FILD) is a general term that includes many diseases that manifest as pulmonary fibrosis and are often progressive and associated with high morbidity. However, there are limited data regarding the frequency and prognosis of FILD patients other than those with idiopathic pulmonary fibrosis (IPF). The purpose of this study was to investigate the clinical characteristics and early prognostic risk factors for FILD. This study retrospectively reviewed the data of patients who were diagnosed with FILD between April 2011 and September 2022 in our centre. Ultimately, 194 patients diagnosed with non-IPF fibrotic ILD were screened in our study. Baseline clinical information, pulmonary function tests, and chest images were collected and analysed. Connective tissue disease-related interstitial lung disease (CTD-ILD) (60.3%) was the most common subgroup of FILD and associated with longer survival than the other types of FILD. The age at diagnosis of ILD (64.4 ± 13.5 vs. 70.0 ± 11.6 years, P = 0.001) and the proportion of males, smokers and acute exacerbations (AEs) (13.5% vs. 27.5%, P = 0.026) were significantly higher in the UIP group than in the NSIP group. The Kaplan‒Meier survival analysis showed that the IPF group (HR 1.97, 95% CI 1.05–3.70, P = 0.011) had a worse survival rate than the FILD group, and landmark analyses showed that the survival of FILD patients with the UIP pattern (HR 3.07 95% CI 1.37–6.86 P = 0.006) was significantly shorter than that of FILD patients with the NSIP pattern 48 months after ILD diagnosis. In the multivariate Cox analysis, AEs of ILD (HR 4.17 95% CI 2.24–7.75 P < 0.001) and combined with lung cancer (HR 3.12 95% CI 1.27–7.65 P = 0.013) remained as significant factors that were independently associated with shorter survival. CTD-ILD is the most common subgroup of FILD in our study, and the prognosis is better than that of other types of FILD. Patients with the UIP pattern tend to be older and have a higher proportion of AEs. The prognosis is worse than that of patients with the NSIP pattern in the later stage. AEs and combined with lung cancer are independent risk factors for the prognosis of FILD patients, and more attention should be given to such patients.

PMID:40596620 | PMC:PMC12215683 | DOI:10.1038/s41598-025-08969-1

Intern Med. 2025 Jul 3. doi: 10.2169/internalmedicine.5369-25. Online ahead of print.

ABSTRACT

A 70-year-old man with idiopathic pulmonary fibrosis undergoing nintedanib treatment for 2 years experienced worsening diarrhea, which prompted colonoscopy. An examination revealed a coarse mucosal appearance and erosion extending from the rectum to the ascending colon with linear mucosal defects in the sigmoid colon. Histopathological findings from the biopsies demonstrated features resembling those of collagenous colitis (CC). The diarrheal symptoms resolved rapidly after nintedanib withdrawal. The patient was subsequently diagnosed with nintedanib-associated, drug-induced colitis with CC-like features. Although linear mucosal defects linked to proton pump inhibitors, particularly lansoprazole, have been reported in CC, they have not been previously described in nintedanib-associated colitis.

PMID:40603092 | DOI:10.2169/internalmedicine.5369-25

Eur Respir J. 2025 Jul 2;65(6):25E6506. doi: 10.1183/13993003.E6506-2025. Print 2025 Jun.

NO ABSTRACT

PMID:40602829 | DOI:10.1183/13993003.E6506-2025

Br J Nurs. 2025 Jul 3;34(13):675-682. doi: 10.12968/bjon.2024.0432.

ABSTRACT

With escalating demands and economic limitations in the health sector, the Irish government has implemented a strategy to increase the number of advanced nurse practitioners caring for patients with interstitial lung disease (ILD). There are more than 200 different types of ILD, which are identified by features such as inflammation and fibrosis of the lung interstitium. Idiopathic pulmonary fibrosis (IPF) is the most common; it is a life-limiting lung disease with a median survival period of 3-5 years. Symptoms include breathlessness, cough, fatigue and anxiety. Treatment options are limited, and include medications to slow progression, exercise and oxygen therapy. Patient care has advanced as a result of using evidence-based practice set out in National Institute for Health Excellence guidelines and the Irish Thoracic Society position statement on IPF. The availability of resources and patient preferences can influence treatment options. The respiratory advanced nurse practitioner is in a unique position to manage the care of the person with IPF holistically, through patient education, symptom management, pulmonary rehabilitation and palliative care. The development of a national clinical care programme for ILD could facilitate standardised care and outcomes for patients.

PMID:40601554 | DOI:10.12968/bjon.2024.0432

Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul 2. doi: 10.1007/s00210-025-04270-0. Online ahead of print.

ABSTRACT

To explore the therapeutic effects of Nobiletin (NOB) on Idiopathic pulmonary fibrosis (IPF) and to identify its targets and molecular pathways. We verified the inhibitory effect of NOB on the senescence of A549 cells through in vitro experiments, and the inhibitory effect of NOB on the migration ability of fibroblasts was verified by the Transwell experiment. The inhibitory effects of NOB on Idiopathic IPF were subsequently assessed in a mouse model induced by bleomycin (BLM). Through PPI network, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the PI3K/AKT/MDM2/p53 signaling pathway was identified as the critical pathway. The key proteins in the signaling pathway were verified by molecular docking and western blotting. NOB showed a great inhibitory effect on A549 cell senescence and Fibroblast migration. Meanwhile, NOB reduced BLM-induced collagen deposition in mouse lung tissues and inhibited alveolar epithelial cell (AEC) senescence. Through PPI network, P53 was screened as a core target of NOB. According to functional enrichment analysis results, the PI3K/AKT signaling was believed to have played an important role. Therefore, we speculate that the PI3K/AKT/MDM2/p53 signaling pathway mediated NOB's impact on IPF. These findings were validated through molecular docking and western blotting. This study demonstrated that NOB suppressed cell senescence to protect IPF through mediating the PI3K/AKT/MDM2/p53 signaling pathway.

PMID:40600992 | DOI:10.1007/s00210-025-04270-0

Biol Direct. 2025 Jul 1;20(1):76. doi: 10.1186/s13062-025-00670-7.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive macrophage infiltration and extracellular matrix deposition. The progress of IPF is promoted by M2 macrophages which produce pro-fibrotic factors and induce fibroblast differentiation. SESN3 was upregulated in lung tissues of IPF patients and mice with bleomycin-induced pulmonary fibrosis. However, the role of SESN3 in IPF and its related mechanisms remain largely unknown.

METHODS: Here, we used IL-4/13 to induce macrophage M2 polarization in RAW264.7 cells and constructed a mouse model of pulmonary fibrosis by intratracheal injection of bleomycin. Adenoviruses targeting SESN3 were constructed to infect RAW264.7 cells and BLM-induced mice to assess the function of SESN3 in macrophage M2 polarization in the progress of IPF and mRNA-seq and Co-IP-MS analysis were performed to find the downstream factors.

RESULTS: For in vitro experiments, SESN3 knockdown promoted the M2 polarization level, the release of pro-fibrosis factors and the activation of fibroblast, overexpression of SESN3 had an opposite trend. For in vivo experiments, the increased degree of pulmonary fibrosis in BLM mice was relieved after overexpression of SESN3. Meanwhile, overexpression of SESN3 repressed the increased macrophage M2 polarization level induced by BLM. Mechanically, FOSL2 was screened out through mRNA-seq and Co-IP-MS analysis due to its binding affinity with SESN3 and the observed downregulation of its downstream pro-fibrotic factor expression. The expression of FOSL2 in the nucleus was down-regulated after SESN3 overexpression. Under IL-4/13 treatment, the increased levels of macrophage M2 polarization and pro-fibrotic factors induced by SESN3 knockdown was recovered after knocking down FOSL2 in RAW264.7 cells.

CONCLUSION: In summary, our study suggested that SESN3 regulated the IPF process through inhibiting macrophage M2 polarization by targeting the activity of FOSL2.

PMID:40597370 | DOI:10.1186/s13062-025-00670-7

Sci Rep. 2025 Jul 2;15(1):22952. doi: 10.1038/s41598-025-04053-w.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-related disease with an unclear pathogenesis. The senescence and insufficient regeneration of alveolar epithelial cells are significant factors in the development and progression of IPF. Currently, effective treatment methods are lacking. The aim of this study is to explore the mechanism of action of uridine in delaying the aging of AECs and intervening in IPF. In vitro, Western blot and qRT-PCR analyzed uridine's effects on bleomycin-induced senescence, EMT, cell viability, and cell cycle. In vivo, uridine's impact on lung aging and fibrosis in BLM-induced mice was assessed by weight, staining, Ashcroft scoring, and Western blot. Uridine reduced senescence markers in A549 cells, suppressed epithelial-mesenchymal transition, improved antioxidant capacity, and delayed pulmonary fibrosis and lung aging in mice. The effects of uridine were mediated through the NRF2 signaling pathway, which regulates antioxidant defense and autophagy. Uridine enhanced autophagic degradation of Keap1, possibly through p62/SQSTM1-mediated autophagy. These findings suggest that uridine inhibits AEC senescence via the NRF2 pathway, mitigating IPF progression and offering a potential strategy for treating age-related pulmonary fibrosis by targeting oxidative stress.

PMID:40594193 | DOI:10.1038/s41598-025-04053-w

Sci Rep. 2025 Jul 1;15(1):21228. doi: 10.1038/s41598-025-02579-7.

ABSTRACT

This study investigates genes linking oxidative stress to idiopathic pulmonary fibrosis (IPF) through multi-omics data integration. We collected oxidative stress-related genes from GeneCards and integrated data for gene expression (eQTLs), DNA methylation (mQTLs), and protein expression (pQTLs). Genome-wide association study (GWAS) data on IPF from Allen et al. served as the discovery set, with FinnGen R10 for validation. Summary data-based Mendelian randomization (SMR) and colocalization analyses assessed interactions and shared causal variants, followed by multi-omics integration with tissue-specific validation. SMR and colocalization screening identified 90 mQTLs, 15 eQTLs, and 2 pQTLs (KRT18 and FOXO1) linked to IPF in the discovery cohort. Twelve mQTLs were validated in the FinnGen cohort, with MUC1 showing strong SMR and colocalization evidence (eQTL). Multi-omics integration validated NDUFA9 (mQTL-eQTL) level and FOXO1 (mQTL-eQTL-pQTL). Our study identified key oxidative stress-related genes (i.e., FOXO1 and NDUFA9) in IPF pathogenesis, highlighting the need for further research to inform prevention and treatment.

PMID:40592928 | DOI:10.1038/s41598-025-02579-7

JCI Insight. 2025 Jul 1:e182578. doi: 10.1172/jci.insight.182578. Online ahead of print.

ABSTRACT

Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously demonstrated that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here, using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a critical component of AT2 cell dysfunction and demonstrate that targeting this druggable signaling hub can rescue the aberrant AT2 cell metabolic phenotype and mitigate lung fibrosis in vivo.

PMID:40591409 | DOI:10.1172/jci.insight.182578