Front Immunol. 2025 Jul 2;16:1541645. doi: 10.3389/fimmu.2025.1541645. eCollection 2025.

ABSTRACT

Extracellular Vesicles (EVs), released by all cell types and detectable in biological samples, carry a variety of biological molecules. These molecules mediate communication and signaling with both local and distant cells, potentially playing a role in the pathogenesis of diseases, including Interstitial Lung Diseases and, more specifically, Idiopathic Pulmonary Fibrosis. To better understand the role of EVs in IPF, a systematic search was performed in PubMed, Scopus, and Ovid databases. These searches were conducted from January 1st, 2019, the period during which the MISEV 2018 guidelines were published, to August 31st, 2024. The SANRA scale was used for quality assessment. A total of 691 papers were screened, and 16, in the end, were definitively enrolled for our evaluation. The studies were reviewed in the following steps: 1) the nomenclature used to define EVs; 2) conformity with the MISEV 2018 guidelines; 3) the biological samples used to isolate EVs; 4) the main conclusion of each manuscript. There was significant heterogeneity among the publications in all the aforementioned steps, such as the type and source of EVs and the analysis of EVs content, primarily a wide array of different miRNAs in the various publications. Despite these differences, the emerging role of EVs and their potential usefulness both in therapies and clinical practice is of growing interest.

PMID:40672958 | PMC:PMC12263404 | DOI:10.3389/fimmu.2025.1541645

Sci Rep. 2025 Jul 17;15(1):25896. doi: 10.1038/s41598-025-12046-y.

ABSTRACT

Previous studies have suggested a potential correlation between obesity and idiopathic pulmonary fibrosis (IPF). This study aimed to elucidate pathogenic pathways connecting obesity and IPF and identify diagnostic biomarkers for obesity-related pulmonary fibrosis. Obesity and IPF datasets were obtained through the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify shared genes for obesity and IPF. Functional enrichment (GO/KEGG), protein-protein interaction (PPI) networks, and machine learning algorithms were applied to screen hub genes, validated by ROC curves. High-fat diet (HFD)-induced obese mice with bleomycin-induced pulmonary fibrosis underwent histological assessment and qRT-PCR validation. Molecular docking evaluated flavonoid binding to hub genes. We identified 128 shared genes between obesity and IPF, predominantly enriched in immune and inflammatory pathways. Machine learning prioritized three hub genes (NLRC4, SPI1, and NCF2), validated by ROC analysis (AUC > 0.7). In animal model, these genes exhibited significant upregulation, correlating with exacerbated fibrosis. Molecular docking highlighted strong binding affinities (-6.3 to -9.6 kcal/mol) between dietary flavonoids and hub targets. Immune-inflammatory dysregulation links obesity and IPF via NLRC4, SPI1, and NCF2. These genes serve as diagnostic biomarkers and therapeutic targets, with flavonoids showing intervention potential. Our findings advance mechanistic insights into obesity-related pulmonary fibrosis.

PMID:40670650 | DOI:10.1038/s41598-025-12046-y

Rev Med Chil. 2025 Jul;153(7):527-538. doi: 10.4067/s0034-98872025000700527.

ABSTRACT

Interstitial lung diseases are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lung parenchyma, leading to a progressive loss of lung function. Idiopathic pulmonary fibrosis (IPF) is a representative model with a pathophysiology common to other types of pulmonary fibrosis.

AIM: This review presents the pathophysiological mechanisms and existing and developing antifibrotic therapies of IPF.

METHOD: Qualitative study through a narrative review of the pathophysiological phenomena of IPF and advances in antifibrotic therapy.

RESULTS: The role of the alveolar epithelium, fibroblast/myofibroblast activity, cellular senescence and aging, immune system activity, oxidation-reduction mechanisms and genetic characteristics have been identified, which reveal the complex pathophysiology of this disease. Currently, there are only two therapies available to mitigate the effects of pulmonary fibrosis, Pirfenidone and Nintedanib, and the development and research of other antifibrotic drugs is still pending.

CONCLUSIONS: There are multiple pathophysiological phenomena in IPF. Understanding them is the basis for the development and evolution of antifibrotic therapies.

PMID:40668019 | DOI:10.4067/s0034-98872025000700527

bioRxiv [Preprint]. 2025 Jun 21:2025.06.10.658504. doi: 10.1101/2025.06.10.658504.

ABSTRACT

Acute and repetitive lung epithelial injury can lead to irreversible and even progressive pulmonary fibrosis; Idiopathic pulmonary fibrosis (IPF) is a fatal disease and quintessential example of this phenomenon. The composition of epithelial cells in human pulmonary fibrosis - irrespective of disease etiology - is marked by the presence of Aberrant Basaloid cells: an abnormal cell phenotype with pro-fibrotic and senescent features, localized to the surface of fibrotic lesions. Despite their relevance to human pulmonary fibrosis, the exotic molecular profile of Aberrant Basaloid cells has obscured their etiology, preventing insights into how or why these cells emerge with fibrosis. Here we identify cellular intermediaries between Aberrant Basaloid and normal alveolar epithelial cells in human IPF tissue. We track the emergence of Aberrant Basaloid cells from alveolar epithelial cells ex vivo and uncover a role for similar cells in epithelial regeneration under normal conditions. Lastly, we characterize the epigenetic changes that distinguish Aberrant Basaloid cells from their progenitors and identify hallmarks of AP-1 injury memory retention. This study elucidates the phenomenon of maladaptive epithelial plasticity and regeneration in pulmonary fibrosis and re-contextualizes therapeutic strategies for epithelial dysfunction.

PMID:40667263 | PMC:PMC12262340 | DOI:10.1101/2025.06.10.658504

bioRxiv [Preprint]. 2025 Jun 21:2025.06.16.659944. doi: 10.1101/2025.06.16.659944.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic pulmonary disease with unknown etiology. Since approved idiopathic pulmonary fibrosis (IPF) drugs only slow disease progression, novel therapeutics are required that improve clinical outcomes. Here, we report a single cell RNA-Seq and regulatory network analysis of the largest IPF cohort assembled to date. Segregating this cohort based on status of treatment with approved antifibrotics (untreated, nintedanib- and pirfenidone-treated), we describe for the first time the transcriptional landscape of untreated IPF across 40 lung cell types, and the elements of this program that are impacted by approved antifibrotics. On average, 60% of the untreated IPF-dysregulated transcriptome is refractory to treatment with these drugs, a transcriptional deficit we refer to as the IPF therapeutic gap. Regulatory network analysis indicated a dominant functional footprint for the transcription factor STAT3 in both untreated IPF and in the IPF therapeutic gap. Validating our analysis in a translational precision cut lung slice platform that recapitulates IPF explants, treatment with a STAT3 inhibitor reduced the IPF therapeutic gap in numerous lung cell types. Finally, we implicated STAT3 as a master transcription factor that regulates a network comprising numerous profibrotic transcription factors in IPF alveolar fibroblasts, a critical fibrotic cell lineage. Our study represents a comprehensive resource for translational lung fibrosis research and establishes a novel strategy for drug discovery in human disease more broadly.

PMID:40666833 | PMC:PMC12262394 | DOI:10.1101/2025.06.16.659944

Biol Direct. 2025 Jul 15;20(1):83. doi: 10.1186/s13062-025-00658-3.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive pulmonary disease characterized by alveolar structural destruction and fibrosis. In recent years, efferocytosis has been recognized as playing a crucial role in the occurrence and progression of IPF. This study aimed to identify and regulate key efferocytosis-related genes to elucidate their potential roles and clinical significance in IPF.

METHODS: IPF-related datasets (GSE32537) were obtained from the Gene Expression Omnibus (GEO) database. Differential gene expression analysis and weighted gene coexpression network analysis (WGCNA) were applied to identify key genes associated with IPF, intersecting them with efferocytosis-related genes (ERGs) to obtain IPF-ERGs. Protein‒protein interaction (PPI) network construction and enrichment analysis were performed to elucidate the potential functions of these genes in IPF. Seven machine learning algorithms were employed to screen for hub genes with high diagnostic value. The GSE70866 dataset was used for validation, and a nomogram was constructed. Additionally, the CIBERSORT algorithm was used to analyze immune infiltration levels, and transcriptomic validation of the hub genes was conducted in animal experiments.

RESULTS: A total of 21 IPF-ERGs were identified, and machine learning further identified TLR2, ATG7, SPHK1, and ICAM1 as hub genes, which were significantly upregulated in the IPF group. Immune infiltration analysis revealed a significant increase in the infiltration levels of immune cell subsets, including memory B cells, CD8 + T cells, and resting dendritic cells, in the IPF group. Further clinical correlation analysis revealed a strong association between the expression levels of the hub genes and pulmonary function. A nomogram was constructed on the basis of the hub genes and validated for its potential clinical application. Consensus clustering classified IPF patients into two subtypes: C1, which was primarily by metabolic pathway activation, and C2, which was enriched in inflammatory and immune pathways. Transcriptomic analysis of animal experiments also confirmed the upregulation of hub gene expression in IPF.

CONCLUSION: This study identified TLR2, ATG7, SPHK1, and ICAM1 as four key hub genes, revealing their potential diagnostic value and biological functions in IPF. These genes may serve as potential diagnostic biomarkers and therapeutic targets, providing new insights for precision treatment.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:40665394 | DOI:10.1186/s13062-025-00658-3

EJNMMI Radiopharm Chem. 2025 Jul 15;10(1):44. doi: 10.1186/s41181-025-00366-3.

ABSTRACT

BACKGROUND: Lung diseases such as idiopathic pulmonary fibrosis and acute respiratory distress syndrome (ARDS) are associated with significant morbidity and mortality, with limited treatment options. Platelet-derived growth factor receptor beta (PDGFRβ) signaling pathway is a key driver of fibrogenesis in different organs. In the lungs, pericytes have a high PDGFRβ expression, and their role as immune regulators and progenitors of myofibroblasts is increasingly recognized. Non-invasive techniques to assess active lung tissue remodeling are needed to improve disease monitoring and treatment evaluation. This study aimed to evaluate [18F]TZ-Z09591, targeting PDGFRβ, for imaging pulmonary injuries in human biopsies, and in vivo in animal models of lung injury.

RESULTS: [18F]TZ-Z09591 demonstrated high and specific binding to PDGFRβ-expressing cells. Autoradiography confirmed tracer uptake in lung injuries, including fibrotic foci, from human, rat, and pig lung tissues. In vivo positron emission tomography (PET) imaging of bleomycin-induced lung fibrosis in rats and an ARDS pig model showed significantly increased uptake in diseased lung segments compared to controls, especially in pulmonary injuries with collagen deposition, despite moderate background uptake.

CONCLUSIONS: This study demonstrated that [18F]TZ-Z09591 can assess PDGFRβ expression in pulmonary injuries, supporting its potential for non-invasive assessment of lung tissue remodeling. PET imaging targeting PDGFRβ could improve disease monitoring, and provide new insights into pulmonary fibrosis progression.

PMID:40664934 | DOI:10.1186/s41181-025-00366-3

Front Aging. 2025 Jun 30;6:1604051. doi: 10.3389/fragi.2025.1604051. eCollection 2025.

ABSTRACT

INTRODUCTION: The receptor for hyaluronan-mediated motility (RHAMM), a centrosomal protein expressing in multiple isoforms, is implicated in telomerase-independent aging. However, its involvement in telomerase regulation is unproven. This study aims to investigate whether RHAMM correlates with telomerase activity in mammalian cells.

METHODS: Mouse embryonic fibroblasts expressing or lacking full-length RHAMM (RHAMMFL, amino acids 1-794) and the shorter isoform RHAMMΔ163 (amino acids 164-794), were explored to examine the effect of RHAMM isoforms on mRNA expression of telomerase reverse transcriptase (TERT) and selective shelterin proteins regulating telomere maintenance.

RESULTS: The preliminary findings revealed that RHAMM regulated Tert expression based on its isoforms. RHAMMΔ163 enhanced Tert mRNA expression and promoted telomerase activity by stimulating sirtuin 1 (Sirt1), shelterin proteins Tpp1, and Pot1a and repressing the telomerase inhibitor Pinx1 levels. In contrast, RHAMMFL did not have significant effect on TERT expression and telomerase activity. Increasing Tert mRNA expression by blocking leucine zipper sequence with function-blocking RHAMM peptide NP-110 in a TERT-deficient mouse model of idiopathic pulmonary fibrosis, alongside suppressing Tpp1 and Pot1a expression in mouse embryonic fibroblasts using ERK1 inhibitor PD98059, highlights the importance of the HATABD domain (amino acids 718-751), which includes leucine zipper and ERK-binding sequences at the C-terminus of mouse RHAMM in regulating telomerase function. Increased telomerase activity raised Hmmr expression, suggesting a potential feedback loop between RHAMM and TERT expression.

DISCUSSION: Taken together, this report provides the first evidence that RHAMMΔ163 regulates TERT and shelterin expression and telomerase activity in mammalian cells.

PMID:40661163 | PMC:PMC12256479 | DOI:10.3389/fragi.2025.1604051

Medicine (Baltimore). 2025 Jul 11;104(28):e43102. doi: 10.1097/MD.0000000000043102.

ABSTRACT

Recent studies have suggested an increased incidence of various lung diseases following COVID-19 vaccination. However, causal relationships have not been definitively established. We conducted a two-sample Mendelian randomization (MR) study using publicly available genome-wide association study data to investigate potential causal relationships between COVID-19 vaccination status as the exposure and 14 different lung diseases as outcomes. The analytical methods included random-effects inverse-variance weighting, MR Egger, and weighted median, with additional heterogeneity and sensitivity analyses. Seven instrumental variables for exposure were selected (P < 5 × 10-8). MR analyses revealed that COVID-19 vaccination status was not associated with an increased risk of developing overall lung cancer (P = .78), lung adenocarcinoma (P = .557), squamous cell lung cancer (P = .557), non-small cell lung cancer (P = .173), asthma (P = .905), chronic obstructive pulmonary disease, bronchiectasis (P = .669), forced vital capacity (FVC), forced expiratory volume in 1 second/FVC (P = .794), pneumonia (P = .282), idiopathic pulmonary fibrosis (P = .486), pulmonary embolism (P = .267), pneumothorax (P = .73), or sarcoidosis (P = .732). Evidence of heterogeneity was observed in the inverse-variance weighting model for overall lung cancer, chronic obstructive pulmonary disease, and FVC, whereas no indications of horizontal pleiotropy or significant heterogeneity were noted for other lung diseases. COVID-19 vaccination does not appear to increase the risk of developing various lung diseases. These findings support the safety of COVID-19 vaccines in terms of respiratory health, reinforcing their role in public health interventions and vaccination policies.

PMID:40660535 | DOI:10.1097/MD.0000000000043102

Nano Lett. 2025 Jul 14. doi: 10.1021/acs.nanolett.5c02481. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease and is one of the complications observed in individuals following COVID-19 infection. Although inhalable nanomedicines hold promise, nebulization-induced shear stress, dense airway mucus barrier, and inefficient in vivo clearance substantially compromise nanomedicine delivery efficiency and biosafety, thereby limiting their therapeutic efficacies. Herein, an inhalable microenvironment-responsive hybrid nanomedicine (PFD@FPNs-CAT) encapsulated with pirfenidone (PFD) and modified with catalase (CAT) is developed, which is able to overcome the supramolecular interactions owing to the small particle size, electronegativity, and PEGylated surface, thus enhancing the accumulation of PFD@FPNs-CAT in the lesions. Moreover, the surface-anchored CAT is demonstrated to relieve hypoxia, thus reversing the immunosuppressive microenvironment and further enhancing the therapeutic efficacy against IPF. Notably, due to the relatively low quantity of silica doping, PFD@FPNs-CAT demonstrates high stability and excellent biocompatibility. This inhalable mucus-penetrating nanomedicine remarkably inhibits the progression of IPF, illuminating the bright prospects for IPF therapy.

PMID:40657744 | DOI:10.1021/acs.nanolett.5c02481

Int J Med Sci. 2025 Jun 12;22(12):2992-3006. doi: 10.7150/ijms.113226. eCollection 2025.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a chronic progressive fibrosing interstitial lung disease with an unclear etiology, is characterized by progressive respiratory impairment and a median survival of 3-5 years. The pathophysiology associated with genetic factors in IPF remains largely unknown, despite the fact that both familial and sporadic IPF exhibit genetic susceptibility. In this review, we comprehensively examine genetic variations associated with the functional roles of mucin 5B (MUC5B), telomerase complex, surfactant proteins, cytokines, signaling pathways, and epigenetic mechanisms. A multifaceted perspective derived from genetic, epidemiological, and clinical studies demonstrates that genetic variations exert differential impacts on the development, progression, and prognosis of IPF. We advocate for the application of genetic knowledge to facilitate the refinement of diagnostic approaches, enhance the assessment of therapeutic strategies and prognostic outcomes, and underscore the significance of personalized therapy for IPF.

PMID:40657392 | PMC:PMC12244033 | DOI:10.7150/ijms.113226

Front Immunol. 2025 Jun 27;16:1583827. doi: 10.3389/fimmu.2025.1583827. eCollection 2025.

ABSTRACT

BACKGROUND: Neurological symptoms are commonly observed in patients with idiopathic pulmonary fibrosis (IPF). However, the underlying mechanisms remain unclear. Although exercise has been shown to improve pulmonary fibrosis and quality of life in IPF patients, its effects on neurological symptoms in this population are not well understood. Furthermore, a robust animal model linking IPF with comorbid neurological symptoms has not yet been fully developed.

METHODS: Twenty-eight male C57BL/6J mice were divided into four groups: control, bleomycin (BLM), control + exercise, and BLM + exercise. Mice were administered BLM or saline (7.5 mg/kg), and the exercise groups underwent 45 min of treadmill training per day for 28 days. Behavioral tests (open-field test, sucrose preference test, tail suspension test, and forced swimming test) were performed on days 29-33. Histological analysis assessed pulmonary fibrosis, and biomarkers brain-derived neurotrophic factor (BDNF) and c-Fos were detected. Bioinformatics identified genes altered in IPF, exercise, and depression, validated by Western blotting.

RESULTS: BLM induced pulmonary fibrosis and aggravated neurological symptoms. Exercise significantly alleviated these symptoms and reversed the expression of BDNF and c-Fos. Bioinformatics analysis identified 28 genes upregulated in IPF and depression and downregulated by exercise. The S100A12 gene showed reduced expression in both lung and brain tissues in the BLM group and increased expression after exercise. Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment in the Interleukin 17 (IL-17) and Nucleotide-binding Oligomerization Domain (NOD)-like receptor signaling pathways.

CONCLUSION: This study developed a mouse model and suggests that exercise may offer therapeutic benefits for both pulmonary and neurological symptoms in IPF. Shared molecular pathways may guide future therapies targeting both aspects.

PMID:40655156 | PMC:PMC12245693 | DOI:10.3389/fimmu.2025.1583827

Acta Pharm Sin B. 2025 Jun;15(6):3041-3058. doi: 10.1016/j.apsb.2025.04.017. Epub 2025 Apr 22.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

PMID:40654335 | PMC:PMC12254822 | DOI:10.1016/j.apsb.2025.04.017

Int J Mol Sci. 2025 Jul 7;26(13):6538. doi: 10.3390/ijms26136538.

ABSTRACT

Emerging evidence suggests a significant association between monocytes and the pathophysiology and prognosis of idiopathic pulmonary fibrosis (IPF). This review aims to systematically evaluate current knowledge regarding blood monocyte counts and their relationship with the etiology, progression, and prognosis of IPF. We conducted a systematic search in the PubMed database for articles published through 17 February 2025, using the MeSH terms "lung diseases, interstitial" and "monocytes," which yielded 314 results. After filtering for full-text articles in English (n = 242), we included only studies focusing on blood monocyte counts with clinical implications in IPF. Articles relating to other cell types or non-IPF lung diseases were excluded. Our systematic search identified 12 relevant articles. Monocytes play an essential role in regulating inflammatory responses and resolution across multiple diseases, with established but incompletely understood contributions to lung fibrosis development in IPF. Correlations have been demonstrated between elevated blood monocyte counts and the following: (1) the presence and progression of interstitial lung abnormalities, (2) the progression from an indeterminate usual interstitial pneumonia (UIP) pattern on CT scans to definitive IPF, and (3) worse lung function parameters, an increased risk of acute exacerbations, and reduced overall survival in IPF patients. Monocytes serve as critical orchestrators throughout IPF's natural history-from early interstitial changes to disease progression and acute exacerbations. Targeting monocyte recruitment pathways and reprogramming their differentiation represents a promising therapeutic approach, while circulating monocyte counts offer potential as accessible biomarkers for disease progression and treatment response. Future research should characterize stage-specific monocyte phenotypes to enable precision-targeted interventions.

PMID:40650314 | DOI:10.3390/ijms26136538

Int J Mol Sci. 2025 Jun 27;26(13):6202. doi: 10.3390/ijms26136202.

ABSTRACT

The uncontrolled fibrosis of lung tissue can lead to premature death in patients suffering from idiopathic pulmonary fibrosis (IPF), and it complicates the course of chronic obstructive pulmonary disease (COPD) and emphysema. It is also a risk factor for developing lung cancer. Antifibrotic drugs, such as nantedanib and pirfenidone, are able to slow down the progression of pulmonary fibrosis, but more effective treatment is still needed to reverse it. Studies on the pathogenesis of tissue fibrosis have demonstrated that integrins play a crucial role affecting the development of pulmonary fibrosis, for example, by activating transforming growth factor-β (TGF-β). Taking the above into consideration, targeting specific integrins could offer promising opportunities for managing fibroplastic changes in lung tissue. Integrins are a type of transmembrane molecule that mediate interactions between cells and extracellular matrix (ECM) molecules. This review discusses the role of integrins in the pathogeneses of respiratory diseases and carcinogenesis, as well as presents promising approaches to the drug therapy of pulmonary fibrosis of various etiologies based on integrin inhibition.

PMID:40649983 | DOI:10.3390/ijms26136202

Toxicology. 2025 Jul 9:154233. doi: 10.1016/j.tox.2025.154233. Online ahead of print.

ABSTRACT

Pulmonary fibrosis, a progressive and debilitating disease, presents a significant global health challenge. Even though often idiopathic, drug-induced fibrosis is increasing its incidence. Traditional chemical safety assessments, relying on apical endpoints from in-vivo models, are limited in capturing the early molecular events initiating fibrosis, consequently limiting the potential for early diagnosis and mechanism-driven treatment. This study employed a toxicogenomic approach on in-vitro MRC-5 fibroblasts, a crucial cell type involved in fibrosis, to dissect the initiating profibrotic mechanisms of Bleomycin (1, 1.5, 2 ug/mL), a profibrotic triggering stimulus, comparing it with TGFβ-1(5, 10, 15ng/mL), a known sustaining mediator of fibrosis over 24, 48, and 72hours. Our analysis reveals that while both agents alter matrix-related processes, their initiation mechanisms diverge. Specifically, TGFβ-1 directly induces myofibroblast transition, whereas Bleomycin potentially induces an indirect transition through the establishment of a senescence-associated secretory phenotype (SASP). By capturing the early SASP signature, we identified a critical driver of Bleomycin-induced fibroblast fibrosis, relevant to drug-induced fibrosis where antineoplastic agents are a major concern. This study underscores the critical importance of integrating mechanistic understanding into chemical safety assessment, thereby facilitating the development and implementation of safer, more sustainable chemical development.

PMID:40645554 | DOI:10.1016/j.tox.2025.154233

Int Immunopharmacol. 2025 Jul 10;162:115182. doi: 10.1016/j.intimp.2025.115182. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by excessive extracellular matrix (ECM) accumulation, fibroblast activation, and chronic inflammation. This study examined the antifibrotic effects of naltrexone (NTX), an opioid receptor antagonist, in a bleomycin (BLM)-induced pulmonary fibrosis model in Wistar rats. Daily administration of NTX significantly reduced alveolar wall thickening, collagen deposition, and histopathological injury scores. At higher doses, NTX markedly decreased levels of pro-inflammatory cytokines (TNF-α, IL-6, TGF-β), oxidative stress markers (MPO, NO), and key fibrotic markers including α-SMA and delta opioid receptor (DOR). Additionally, NTX restored antioxidant defenses (GSH, TAC) and enhanced GSK-3β phosphorylation, thereby modulating the Wnt/β-catenin and NF-κB signaling pathways. To further investigate the cellular mechanisms underlying NTX's antifibrotic activity, in vitro experiments were conducted using BLM-stimulated NIH-3 T3 fibroblasts. NTX inhibited the production of collagen type I and III, tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and matrix metalloproteinases (MMP-2 and MMP-9) in a dose- and time-dependent manner. This dual regulation of ECM synthesis and degradation suggests a more balanced therapeutic strategy compared to merely inhibiting collagen accumulation. Molecular docking analyses revealed strong interactions between NTX and key proteins involved in inflammatory and fibrotic signaling cascades. Notably, NTX at a dose of 20 mg/kg demonstrated antifibrotic efficacy comparable to that of pirfenidone. Collectively, these findings suggest that NTX exerts protective effects in pulmonary fibrosis by simultaneously targeting inflammation, oxidative stress, and ECM remodeling. Given its favorable tolerability and potential cost-effectiveness, NTX emerges as a promising candidate for IPF therapy. Further clinical investigations are warranted to evaluate its translational potential.

PMID:40644860 | DOI:10.1016/j.intimp.2025.115182

Tissue Barriers. 2025 Jul 11:2532160. doi: 10.1080/21688370.2025.2532160. Online ahead of print.

ABSTRACT

This review describes similarities between the biological actions of cell adhesion molecule antagonists and pan-growth factor receptor tyrosine kinase (GF-RTK) antagonists. In particular, the biological consequences of the interaction between the cell adhesion molecule, neural (N)-cadherin (CDH2) and the fibroblast GF-RTK (FGF-RTK) are discussed. Intercellular adhesion mediated by N-cadherin stimulates FGF-RTK activity triggering intracellular signaling pathways (e.g. PI3/Akt/mTOR pathway) that regulate various morphogenetic processes (e.g. apoptosis). Antagonists of either N-cadherin or GF-RTKs modulate these processes. N-cadherin antagonists can be regarded as a previously unappreciated class of FGF-RTK inhibitors. These antagonists, similar to GF-RTK antagonists should be capable of serving as therapeutics for treating a variety of fibrotic diseases and cancers.

PMID:40642775 | DOI:10.1080/21688370.2025.2532160

Front Mol Biosci. 2025 Jun 26;12:1596364. doi: 10.3389/fmolb.2025.1596364. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease that worsens over time, culminating in respiratory failure. Emerging evidence implicates dysregulated energy metabolism in driving fibroblast activation and extracellular matrix remodeling during IPF pathogenesis. To systematically investigate metabolic reprogramming mechanisms, we performed integrated bioinformatics analyses focusing on energy metabolism-related differentially expressed genes (EMRDEGs) and their regulatory networks in fibrotic remodeling.

METHODS: Differentially Expressed Genes (DEGs) were identified by accessing datasets GSE242063 and GSE110147 from the GEO database. Energy metabolism-related genes (EMRGs) were extracted from GeneCards, followed by Venn diagram analysis to obtain EMRDEGs. Subsequent analyses included functional enrichment (GO/KEGG), protein-protein interaction network, and mRNA-miRNA, mRNA-transcription factor interaction networks. Immune infiltration analyses, including the CIBERSORT algorithm, and single-sample gene set enrichment analysis (ssGSEA), were subsequently conducted.

RESULTS: We identified 12 EMRDEGs and eight hub genes (ACSL1, CEBPD, CFH, HMGCS1, IL6, SOCS3, TLR2, and UCP2). Regulatory network analysis revealed HMGCS1 as a novel IPF-associated gene interacting with PPARα signaling, while SOCS3 coordinated multiple hub genes (IL6, CEBPD, UCP2, and CFH) through FOXA1/2-mediated transcriptional regulation alongside JAK/STAT3 pathway suppression. Immune profiling demonstrated significant hub gene-immune cell correlations, particularly neutrophil-mediated differential gene expression and microenvironment remodeling.

CONCLUSION: The core EMRDEGs (HMGCS1 and SOCS3) and prioritized pathways (PPARα signaling, FOXA networks, JAK/STAT3 suppression) elucidate metabolic reprogramming mechanisms in fibrotic progression. These molecular signatures provide novel clinical biomarkers for IPF diagnosis.

PMID:40642530 | PMC:PMC12241802 | DOI:10.3389/fmolb.2025.1596364

Respirol Case Rep. 2025 Jul 9;13(7):e70270. doi: 10.1002/rcr2.70270. eCollection 2025 Jul.

ABSTRACT

Hypereosinophilic Syndrome (HES) represents a heterogeneous and complex group of disorders characterised by persistent blood and tissue eosinophilia, leading to progressive tissue damage and organ dysfunction. This spectrum includes both hematologic variants and non-hematologic forms, either secondary to identifiable causes or idiopathic in nature. In this article, we describe a rare clinical presentation of HES manifesting primarily with pulmonary involvement, diagnosed as Non-Specific Interstitial Pneumonia (NSIP). Remarkably, the interstitial lung disease showed near-complete reversibility following targeted inhibition of the IL-5 pathway with mepolizumab, highlighting the potential role of Th2-driven eosinophilic inflammation in the pathogenesis of certain forms of interstitial lung disease.

PMID:40641495 | PMC:PMC12241705 | DOI:10.1002/rcr2.70270