Sci Rep. 2025 Apr 5;15(1):11730. doi: 10.1038/s41598-025-94575-0.

ABSTRACT

There are well-documented differences in idiopathic pulmonary fibrosis (IPF) between sexes. The sex-specific prevalence of interstitial lung disease (ILD) subtypes in patients who require a full diagnostic work-up, including transbronchial cryobiopsy (TCB), after initial multidisciplinary discussion (MDD) is still unknown. Retrospective analysis of sex dispareties in patients with ILD who received an interdisciplinary indication for lung biopsy and underwent bronchoalveolar lavage, TCB and, if necessary, surgical lung biopsy at our ILD centre in Heidelberg between 11/17 and 12/21. The analysis included clinical parameters, visual assessment of computed tomography (CT), automated histogram analyses of lung density by validated software and final MDD-ILD classifications. A total of 402 patients (248 men, 154 women; mean age 68 ± 12 years) were analysed. Smoking behaviour was similar between the sexes, but women were more exposed to environmental factors, whereas men were more exposed to occupational factors. Women had higher rates of thyroid disease (29.9% vs. 12.5%; p < 0.001) and extrathoracic malignancies (16.2% vs. 9.3%; p = 0.041), but lower rates of coronary heart disease (7.1% vs. 19.8%; p < 0.001), stroke (1.3% vs. 6.5%; p = 0.014) and sleep apnoea (5.8% vs. 17.7%; p < 0.001). There were no sex differences regarding CT lung density. On visual inspection, women were less likely to have reticular opacities (65% vs. 76%; p = 0.017) and features of usual interstitial pneumonia (17% vs. 34%; p < 0.001). Among final diagnoses, hypersensitivity pneumonitis was more common in women (34.4%) compared to men (21.8%; p = 0.007). In contrast, IPF was more common in men (22.6%) than in women (7.1%; p < 0.001), and unclassifiable interstitial lung disease was also more frequent in men (21.8%) compared to women (6.5%; p < 0.001). This study highlights significant sex-based differences in the prevalence and characteristics of ILD requiring comprehensive diagnostic work-up. These findings underscore the importance of considering sex-specific factors in the diagnosis and management of ILD.

PMID:40188253 | DOI:10.1038/s41598-025-94575-0

Gene. 2025 Apr 3:149464. doi: 10.1016/j.gene.2025.149464. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder that is characterized by the disruption of lung architecture and respiratory failure. Notwithstanding the advent of novel therapeutic agents such as pirfenidone and nintedanib, there remains a pressing need for the development of innovative diagnostic and therapeutic strategies. Next-generation sequencing allows for the analysis of gene expression and the discovery of biomarkers. The objective of our study was to identify IPF-specific gene signatures, construct a diagnostic nomogram, and explore the role of the extracellular matrix (ECM) and epithelial-to-mesenchymal transition (EMT) in IPF pathogenesis. Utilizing data from the Gene Expression Omnibus (GEO) database, we identified differentially expressed genes (DEGs), performed weighted correlation network analysis (WGCNA), and constructed a nomogram. The present study has identified a group of key genes that are associated with IPF. The identified genes include GREM1, ITLN2, MAP3K15, RGS9BP, and SLCO1A2. The results of the immunohistochemical analysis indicated a significant correlation between these central genes and immune cell infiltration. Furthermore, Gene Set Enrichment Analysis (GSEA) revealed that these genes play a critical role in the pathogenesis of IPF. To validate the diagnostic potential of these core genes, we performed confirmatory analyses in independent Gene Expression Omnibus (GEO) datasets. We observed a significant upregulation of GREM1 expression in IPF animal and cellular models. These findings provide new insights into the molecular mechanisms of IPF and suggest potential targets for future diagnostic and therapeutic strategies.

PMID:40187620 | DOI:10.1016/j.gene.2025.149464

Nat Commun. 2025 Apr 5;16(1):3251. doi: 10.1038/s41467-025-58568-x.

ABSTRACT

Inhaled therapeutics have high potential for the treatment of chronic respiratory diseases of high unmet medical need, such as idiopathic pulmonary fibrosis (IPF). Preclinical and early clinical evidence show that cellular communication network factor 2 (CCN2), previously called connective tissue growth factor (CTGF), is a promising target for the treatment of IPF. In recent phase 3 clinical trials, however, systemic CCN2 inhibition failed to demonstrate a clinically meaningful benefit. Here, we present the preclinical profile of the inhaled anti-CCN2 Anticalin® protein PRS-220. Our study demonstrates that efficient pulmonary delivery directly translates into superior efficacy in relevant models of pulmonary fibrosis when compared to systemic CCN2 inhibition. Moreover, we present a holistic approach for the preclinical characterization of inhaled PRS-220 from state-of-the art in vitro and in vivo models to novel human ex vivo and in silico models, highlighting the advantage of inhaled drug delivery for treatment of respiratory disease.

PMID:40185752 | DOI:10.1038/s41467-025-58568-x

Radiother Oncol. 2025 Apr 2:110837. doi: 10.1016/j.radonc.2025.110837. Online ahead of print.

ABSTRACT

The incidence of radiation pneumonitis (RP) has decreased significantly compared to historical series, mainly due to improved radiotherapy techniques and patient selection. Nevertheless, some patients still develop RP. This guideline provides user-friendly flowcharts to address common clinical practice questions regarding RP. We summarize the current state of the art regarding the mechanisms, risk factors, diagnosis and treatment of RP. Dosimetric constraints to minimize the incidence of RP, as well as risk factors for developing RP, such as idiopathic pulmonary fibrosis (IPF) were identified. The combination of radiotherapy and medication as a risk factor for the development of RP was reviewed. RP remains a diagnosis of exclusion, but an algorithm for reaching the diagnosis has been proposed. Finally, practical approaches to the treatment of RP are outlined.

PMID:40185160 | DOI:10.1016/j.radonc.2025.110837

Colloids Surf B Biointerfaces. 2025 Mar 26;252:114652. doi: 10.1016/j.colsurfb.2025.114652. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal, progressive lung disease characterized by extensive scarring and thickening of lung tissue that leads to respiratory failure. Early and accurate diagnosis is crucial for monitoring disease progression and assessing therapeutic efficacy. While imaging modalities such as radiological X-rays and high-resolution computed tomography (HRCT) are commonly employed, magnetic resonance imaging (MRI) offers significant advantages, including superior soft tissue contrast and the absence of ionizing radiation. However, in lung MRIs are hindered by short transverse relaxation times, low proton density, and motion artifacts which is addressed herein by developing theranostic platform combining MRI imaging with targeted drug delivery using melanin nanoparticles conjugated with nintedanib (MNP-NIN). Chelation with ferric ions (MNP-NIN-Fe³⁺) enhanced MRI visibility enabling non-invasive imaging and drug tracking. MNP-NIN and MNP-NIN-Fe³ ⁺ nanoparticles were built with mean diameters of 189 ± 44 nm and 182 ± 35 nm, respectively and demonstrating successful NIN conjugation. Controlled NIN release followed zero-order kinetics over 36 days. MNP conjugation reduced cytotoxicity in BEAS-2B and A549 cells improving the drug's safety. MRI experiments conducted with a 7.0 T animal scanner demonstrated enhanced imaging contrast with MNP-NIN-Fe solutions compared to saline underscoring their potential for localized visualization and tracking within lung tissues. By integrating MRI diagnostics and targeted drug delivery, the MNP-NIN-Fe³ ⁺ system offers a promising solution to overcome current challenges in IPF management. This theranostic platform addresses the limitations of conventional imaging techniques while providing an innovative strategy for reducing drug-related systemic side effects and improving therapeutic efficacy.

PMID:40184721 | DOI:10.1016/j.colsurfb.2025.114652

Front Med (Lausanne). 2025 Mar 20;12:1543571. doi: 10.3389/fmed.2025.1543571. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial lung disease characterized by high mortality rates. An expanding body of evidence highlights the critical role of targeted therapies in the management of IPF. Nevertheless, there is a paucity of bibliometric studies that have comprehensively assessed this domain. This study seeks to examine global literature production and research trends related to targeted therapies for IPF.

METHOD: A literature search was conducted using the Web of Science Core Collection, encompassing publications from 2004 to 2024, focusing on targeted therapies for IPF. The bibliometric analysis utilized tools such as VOSviewer, CiteSpace, and the "bibliometrix" package in R.

RESULTS: A total of 2,779 papers were included in the analysis, demonstrating a general trend of continuous growth in the number of publications over time. The United States contributed the highest number of publications, totaling 1,052, while France achieved the highest average citation rate at 75.74. The University of Michigan Medical School was the leading institution in terms of publication output, with 88 papers. Principal Investigator Naftali Kaminski was identified as the most prolific researcher in the field. The American Journal of Respiratory Cell and Molecular Biology emerged as the journal with the highest number of publications, featuring 98 articles. In recent years, the research has emerged surrounding targeted therapies for IPF, particularly focusing on agents such as TGF-β, pathogenesis, and autotaxin inhibitor.

CONCLUSION: In this bibliometric study, we systematically analyze research trends related to targeted therapies for IPF, elucidating recent research frontiers and emerging directions. The selected keywords-idiopathic pulmonary fibrosis, targeted therapy, bibliometric analysis, transforming growth factor β, and autotaxin inhibitor-capture the essential aspects of this research domain. This analysis serves as a reference point for future investigations into targeted therapies.

PMID:40182841 | PMC:PMC11967194 | DOI:10.3389/fmed.2025.1543571

Immunol Lett. 2025 Aug;274:107006. doi: 10.1016/j.imlet.2025.107006. Epub 2025 Apr 1.

ABSTRACT

OBJECTIVE: This study investigates the involvement of heparanase in IPF pathogenesis and evaluates the therapeutic potential of heparanase inhibition.

METHODS: Plasma heparanase levels were measured in IPF patients and healthy controls. Macrophage infiltration and heparanase expression in bronchoalveolar lavage fluid (BALF) were analyzed using immunofluorescence. Bleomycin (BLM)-induced pulmonary fibrosis mouse models were treated with the heparanase inhibitor OGT2115. Disease severity, macrophage polarization, and heparanase expression were assessed through histological staining, hydroxyproline content measurement, flow cytometry, immunofluorescence, Transmission Electron Microscopy and Western blot analysis.

RESULTS: Elevated heparanase levels were found in the plasma of IPF patients and in macrophages from BALF. In BLM-induced mice, heparanase was predominantly expressed in M2 macrophages. OGT2115 treatment significantly reduced mortality, body weight loss, and fibrosis severity. Additionally, OGT2115 decreased M2 macrophage infiltration, attenuated lung fibrosis, and reduced autophagy markers LC3 I/II and P62.

CONCLUSION: Heparanase plays a crucial role in modulating M2 macrophage polarization and the progression of IPF. Targeting heparanase with OGT2115 effectively ameliorates pulmonary fibrosis and represents a promising therapeutic strategy for IPF management.

PMID:40180131 | DOI:10.1016/j.imlet.2025.107006

Sci Rep. 2025 Apr 3;15(1):11390. doi: 10.1038/s41598-025-90910-7.

ABSTRACT

Pirfenidone is an antifibrotic and anti-inflammatory drug used for the management of idiopathic pulmonary fibrosis. The current oral delivery of PD has multiple drawbacks, including first-pass metabolism and gastrointestinal discomfort. Efforts have been made to create nanostructured lipid carriers (NLCs) using solid lipids, liquid lipids, and surfactants through an emulsification process followed by ultrasonication to achieve sustained drug release. A central composite design (CCD) utilizing response surface methods (RSMs) was employed to develop and optimize the formulation. The assessed characteristics included particle size distribution, surface topography, drug entrapment efficiency, in vitro drug release, and kinetic profiles in animal models. Cytotoxicity experiments were performed on HepG2 and Caco-2 cell lines and compared with that of PD-NLCs. The optimized formulation yielded a particle size of 159.8 ± 3.46 nm and an encapsulation efficiency of 81.4 ± 7.1% after 10 freeze-thaw cycles of homogenized lipid carriers. In vitro tests assessing various tested flow rates revealed that over 95% of the released drug was retrieved. In vitro studies showed that the PD-loaded nanostructured lipid carrier (NLC) was more cytotoxic to HepG2 and Caco-2 cells than a pure aqueous solution of the drug. Using 25% w/w sorbitol as a cryoprotectant, the findings showed no variation in the properties of NLC before and after freeze-drying. PD-NLCs carriers were shown to have better bioavailability, longer retention time in the lung, and a 15.94-targeting factor related to the PD aqueous solution. Hence, the outcomes confirmed the potential of the PD-NLCs formulation to improve the efficacy of the drug in inhalation therapy.

PMID:40181013 | DOI:10.1038/s41598-025-90910-7

Eur Respir J. 2025 Apr 3:2402418. doi: 10.1183/13993003.02418-2024. Online ahead of print.

ABSTRACT

The complex pathogenic relationships between idiopathic pulmonary fibrosis (IPF) and its usually associated comorbidities remain poorly understood. While evidence suggests that some comorbidities may directly influence the development or progression of IPF or vice versa, whether these associations are causal or arise independently due to shared risk factors, such as aging, smoking, lifestyle, and genetic susceptibility, is still uncertain. Some comorbidities, such as metabolic syndromes, gastro-esophageal reflux disease, and obstructive sleep apnea, precede the development of IPF. In contrast, others, like pulmonary hypertension or lung cancer, often become apparent after its onset or during its progression. These timing patterns suggest a directional relationship in their associations. The issue is further complicated by the fact that patients often have multiple comorbidities, which may interact and exacerbate one another, creating a vicious cycle. To clarify these correlations, some studies have used causal inference methods (e.g., Mendelian randomisation) and exploration of underlying mechanisms; however, these efforts have not yet generated conclusive insights. In this review, we provide a general overview of the relationship between IPF and its comorbidities, emphasizing the pathogenic mechanisms underlying each comorbidity, potential shared pathobiology with IPF, and, when available, causal insights from Mendelian randomisation studies.

PMID:40180336 | DOI:10.1183/13993003.02418-2024

Respir Med. 2025 Apr 1:108081. doi: 10.1016/j.rmed.2025.108081. Online ahead of print.

ABSTRACT

BACKGROUND: Abnormal α-Klotho (KL) levels play an essential role in the pathogenesis of aging-related lung diseases. However, the correlation between circulating KL levels and aging-related lung diseases has not been determined. This study aimed to determine whether circulating KL levels causally affect aging-related lung diseases using Mendelian randomization (MR).

METHODS: Five KL-associated Single-nucleotide polymorphisms (SNPs) were analyzed using two-sample MR to assess their effects on three aging-related lung diseases: idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and lung cancer.

RESULTS: Based on a main casual effects model with MR analyses by the inverse variance weighted (IVW) method including multiplicative random-effects model (IVW-mre) and fixed-effects inverse variance-weighted model (IVW-fe), genetically predicted circulating KL levels were negatively related with risk of IPF (Odds ratio (ORIVW-mre), 0.999, 95% CI, 0.999-1.000, PIVW-mre = 0.008; OR IVW-fe, 0.999, 95% CI, 0.999-1.000, PIVW-fe = 0.042). Inversely, the circulating levels of KL displayed no clear association with COPD and lung cancer. No pleiotropy was detected.

CONCLUSIONS: Genetically predicted circulating KL was causally associated with a lower risk of IPF, suggesting a protective effect in preventing IPF risk. Therefore, KL may be a promising target for the prevention and therapeutic intervention in patients with IPF.

PMID:40180194 | DOI:10.1016/j.rmed.2025.108081

STAR Protoc. 2025 Apr 1;6(2):103721. doi: 10.1016/j.xpro.2025.103721. Online ahead of print.

ABSTRACT

Autotaxin (ATX), a secreted lysophospholipase D responsible for the extracellular production of the bioactive phospholipid lysophosphatidic acid (LPA), is a therapeutic target in idiopathic pulmonary fibrosis and pancreatic cancer, among other disorders, promoting the synthesis of novel ATX inhibitors. Here, we present a protocol for detecting and characterizing ATX inhibitors using a fluorometry-based microplate assay. We describe steps for a first screening of compounds, half-maximal inhibitory concentration (IC50) quantification of initial hits, screening for false positives, and identification of the hits' mode of inhibition. For complete details on the use and execution of this protocol, please refer to Stylianaki et al.1.

PMID:40178971 | DOI:10.1016/j.xpro.2025.103721

Eur J Phys Rehabil Med. 2025 Apr 3. doi: 10.23736/S1973-9087.25.08778-7. Online ahead of print.

ABSTRACT

INTRODUCTION: The efficacy of pulmonary rehabilitation (PR) in improving health-related quality of life (HRQoL) in patients with interstitial lung disease (ILD) still have some unresolved issues. This study aimed to identify this gap by using the 36-Item Short Form Survey (SF-36) to assess the advantages and disadvantages of PR in improving the HRQoL of patients with ILD.

EVIDENCE ACQUISITION: Self-controlled before-and-after interventional design research related to PR and ILD published in English were retrieved from PubMed, Embase, Web of Science, Scopus, Ovid, and Cochrane Library from inception to May 19, 2024. Data collected from the included studies were general clinical characteristics, study sample size, SF-36 physical component summary (PCS) score, SF-36 mental component summary (MCS) score, scores of the eight domains (physical function, role physical, bodily pain, general health, vitality, social function, role emotional, and mental health), PR time, and main elements of PR. Subgroup analysis was performed based on the PR time and ILD type. Sensitivity analysis was conducted by excluding one study at a time. Publication bias was assessed using Egger's Test, and the reliability of the studies was determined using the funnel plot and trim-and-fill method. Changes in SF-36 domain scores after PR were presented in a radar chart.

EVIDENCE SYNTHESIS: Pooled analysis of 15 studies involving 1289 patients with ILD who underwent PR showed that the patients had significantly higher PCS scores (weighted mean difference [WMD]=2.07, 95% CI: 1.06, 3.09) and MCS scores (WMD=4.48, 95% CI: 3.21, 5.76) after PR. According to disease types, subgroup analyses showed that patients with idiopathic pulmonary fibrosis had significantly higher PCS scores (WMD=3.15, 95% CI: 0.05, 6.24) but no change in MCS scores after PR (WMD=1.97, 95% CI: -1.91, 5.85). Additionally, subgroup analysis based on PR time revealed that the PCS scores of patients with ILD were significantly increased after <8 weeks of PR (WMD=2.09, 95% CI: 1.02, 3.17) but not after ≥8 weeks of PR (WMD=1.94, 95% CI: -1.05, 4.93, P=0.204). All included studies were of good quality, and the pooled and subgroup results were robust without publication bias.

CONCLUSIONS: In patients with ILD, PR less than 8 weeks effectively improved the physical and mental HRQoL, but not the social function. Future studies should focus on determining the optimal PR time for enhancing HRQoL in patients with ILD and evaluating the efficacy of PR in different ILD types and other HRQoL domains.

PMID:40178411 | DOI:10.23736/S1973-9087.25.08778-7

Respir Res. 2025 Apr 2;26(1):123. doi: 10.1186/s12931-025-03195-9.

ABSTRACT

BACKGROUND: Cardiopulmonary exercise testing (CPET) is feasible, valid, reliable, and clinically useful in interstitial lung disease (ILD). However, maximal CPET values are often presented relative to body mass, whereas fat-free mass (FFM) may better reflect metabolically active muscle during exercise. Moreover, despite the value of maximal parameters, people with ILD do not always exercise maximally and therefore clinically relevant submaximal parameters must be identified. Therefore, this study assessed peak oxygen uptake (VO2peak) relative to FFM, identifying the validity of common scaling techniques; as well as characterising the oxygen uptake efficiency slope (OUES) and plateau (OUEP) as possible submaximal parameters.

METHODS: Participants with ILD underwent assessment of body composition and CPET via cycle ergometry during a single study visit. To determined effectiveness of scaling for body size, both body mass and FFM were scaled using ratio-standard (X/Y) and allometric (X/Yb) techniques. Pearsons's correlations determined agreement between OUES, OUEP, and parameters of lung function. Cohens kappa (κ) assessed agreement between OUES, OUEP and VO2peak.

RESULTS: A total of 24 participants (7 female; 69.8 ± 7.5 years; 17 with idiopathic pulmonary fibrosis) with ILD completed the study. Maximal exercise parameters did not require allometric scaling, and when scaled to FFM, it was shown that women have a significantly higher VO2peak than men (p = 0.044). Results also indicated that OUEP was significantly and positively correlated with DLCO (r = 0.719, p < 0.001), and held moderate agreement with VO2peak (κ = 0.50, p < 0.01).

CONCLUSION: This study identified that ratio-standard scaling is sufficient in removing residual effects of body size from VO2peak, and that VO2peak is higher in women when FFM is considered. Encouragingly, this study also identified OUEP as a possible alternative submaximal marker in people with ILD, and thus warrants further examination.

PMID:40176026 | DOI:10.1186/s12931-025-03195-9

Respir Investig. 2025 Apr 1;63(3):431-437. doi: 10.1016/j.resinv.2025.03.016. Online ahead of print.

ABSTRACT

BACKGROUND: The effect of combining high fraction of inspired oxygen (FIO2) and high flow through a high-flow nasal cannula (HFNC) on exercise tolerance in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) remains unclear.

METHODS: This prospective, single-blind, randomized, crossover study included patients with COPD (n = 25) and IPF (n = 25). The patients performed a 6-min walking test (6 MWT) while attached to a battery-supplied portable HFNC device under the following four conditions: FIO2 set to a minimum percutaneous oxygen saturation (SpO2) of 86-88 % during 6 MWT with a flow rate of 10 L/min (LOLF) or 50 L/min (LOHF); and FIO2 set to a minimum SpO2 of 92-94 % with a flow rate of 10 L/min (HOLF) or 50 L/min (HOHF).

RESULTS: In both groups, the 6-min walking distance (6 MWD) was significantly greater for HOHF than for LOLF (COPD: 323.2 ± 77.6 m vs. 268.6 ± 87.3 m, respectively, p < 0.0001 and IPF: 406 ± 50.7 m vs. 372.3 ± 50.9 m, respectively, p < 0.0001). In the analysis of the interaction effects for the 6 MWD, the combination of high FIO2 and high flow resulted in an additional 15.9-m extension of the 6 MWD (95 % confidence interval: 0.34-31.5; p = 0.050). The interaction between IPF and high-flow was -14.0 m, suggesting a less pronounced extension effect compared with COPD (95 % confidence interval: -29.5-1.6; p = 0.085).

CONCLUSION: The combination of high FIO2 and high flow through an HFNC may improve exercise tolerance in patients with COPD and IPF.

PMID:40174242 | DOI:10.1016/j.resinv.2025.03.016

Eur Rev Med Pharmacol Sci. 2025 Mar;29(3):123-134. doi: 10.26355/eurrev_202503_37125.

ABSTRACT

The interstitial lung disease (ILD) field is rapidly expanding as new insights highlight novel mechanisms and procedures that influence epidemiology, diagnosis, and treatment. The aim of this review is to report on recent advancements and future perspectives in clinical management and research in ILD, particularly in idiopathic pulmonary fibrosis (IPF), for the most common ILD. Whilst high-resolution computed tomography (HRCT) remains the gold standard for diagnosis, we focus on newer diagnostic techniques, including IPF genome analysis and epigenetics, biomarkers, bronchoscope robotic navigation, and transbronchial lung cryo biopsy for improving diagnostic accuracy. Further, we report IPF associated with pulmonary hypertension Group 3 and scores for defining disease progression. Positron emission tomography/computed tomography, treatment with prostacyclin and antifibrotic drugs, and lung transplantation as potential treatments for end-stage IPF are discussed. Lastly, we discuss contemporary perspectives on interstitial lung abnormalities (ILA), IPF associated with lung cancer, and the use of artificial intelligence (AI) for ILD diagnosis and monitoring.

GRAPHICAL ABSTRACT: https://www.europeanreview.org/wp/wp-content/uploads/123-134.jpg.

PMID:40171787 | DOI:10.26355/eurrev_202503_37125

Hereditas. 2025 Apr 1;162(1):50. doi: 10.1186/s41065-025-00401-y.

ABSTRACT

PURPOSE: Ubiquitination plays a crucial role in various diseases. This study aims to explore the potential ubiquitination related genes in IPF.

METHODS: The gene microarray dataset GSE24206 was obtained from GEO database. Subsequently, through differential expression analysis and molecular signatures database, we obtained 1734 differentially expressed genes and 742 ubiquitination related genes. Through the venn diagram analysis, we obtained 53 differentially expressed ubiquitination related genes. Then, gene-ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, protein-protein interactions (PPI) and gene set enrichment analysis (GSEA) were applied for the differentially expressed ubiquitination related genes. Finally, the expression of CDC20 and ITCH in IPF patients and cells were validated by qPCR and western blot assay.

RESULTS: A total of 53 differentially expressed ubiquitination related genes (36 up-regulated genes and 17 down-regulated genes) were identified between 17 IPF patients and 6 healthy controls. GO and KEGG enrichment analysis of ubiquitination related genes mainly involved in regulation of protein ubiquitination, regulation of post-translational protein modification and ubiquitin mediated proteolysis. The PPI results demonstrated that these ubiquitination related genes interacted with each other. The GSEA analysis results for some of the hub genes mainly involved epithelial mesenchymal transition, inflammatory response, hypoxia, and apoptosis. The experiment expression level of CDC20 and ITCH in IPF patients and IPF cells were consistent with the bioinformatics analysis results.

CONCLUSION: We identified 53 potential ubiquitination related genes of IPF through bioinformatics analysis. CDC20 and ITCH and other ubiquitination related genes may influence the development of IPF through epithelial mesenchymal transition and inflammatory response. Our research findings provide insights into the mechanisms of fibrosis and may provide evidence for potential therapeutic targets for fibrosis.

PMID:40170095 | DOI:10.1186/s41065-025-00401-y

J Clin Lab Anal. 2025 Apr 1:e70026. doi: 10.1002/jcla.70026. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial lung disease with a complex pathogenesis involving multiple immune cells. This study investigates the relationship between immune cells and IPF using Mendelian randomization (MR) analysis.

METHODS: A two-sample MR analysis was performed using genome-wide association studies (GWAS) and immune cell databases by R software. We analyzed data from 1028 European individuals with IPF, focusing on 731 immune traits. The primary method of analysis was inverse variance weighting (IVW), supplemented with sensitivity analyses, including MR-Egger regression and MR-PRESSO, to detect and correct for pleiotropy.

RESULTS: The MR analysis identified six immune panels and 23 immune traits significantly associated with IPF, including five traits that increase and 18 traits that decrease IPF risk. Notable traits increasing IPF risk included switched memory B-cells (OR = 1.27, p = 0.0029) and IgD- CD38dim B-cells (OR = 1.08, p = 0.0449). Traits associated with a reduced IPF risk included central memory CD4+ T-cells (%CD4+, OR = 0.96, p = 0.0489), CD20 on naive-mature B-cells (OR = 0.94, p = 0.0499), and CD33br HLA-DR+ absolute count (AC) (OR = 0.93, p = 0.0489). There was no significant causal relationship between IPF disease and some immune traits (p > 0.05).

CONCLUSION: This study suggests a potential causal link between specific immune cell traits and the development of IPF, providing new insights into the disease's immunological mechanisms. Future research should focus on validating these findings in larger, more diverse populations to inform drug development and therapeutic strategies.

PMID:40167279 | DOI:10.1002/jcla.70026

3 Biotech. 2025 Apr;15(4):102. doi: 10.1007/s13205-025-04272-y. Epub 2025 Mar 29.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lung disease with an unknown etiology and a short survival rate. There is no accurate method of early diagnosis, and it involves computed tomography (CT) or lung biopsy. Since diagnostic methods are not accurate due to their similarity to other lung pathologies, discovering new biomarkers is a key issue for diagnosticians. Currently, the use of ccf-DNA (circulating cell-free deoxyribonucleic acid) is an important focus due to its association with IPF-induced alterations in metabolic pathways, such as amino acid metabolism, energy metabolism, and lipid metabolism pathways. Other biomarkers associated with metabolic changes have been found, and they are related to changes in type II/type I alveolar epithelial cells (AECs I/II), changes in extracellular matrix (ECM), and inflammatory processes. Currently, IPF pathogenetic treatment remains unknown, and the mortality rates are increasing, and the patients are diagnosed at a late stage. Signaling pathways and metabolic dysfunction have a significant role in the disease occurrence, particularly the transforming growth factor-β (TGF-β) signaling pathway, which plays an essential role. TGF-β, Wnt, Hedgehog (Hh), and integrin signaling are the main drivers of fibrosis. These pathways activate the transformation of fibroblasts into myofibroblasts, extracellular matrix (ECM) deposition, and tissue remodeling fibrosis. Therapy targeting diverse signaling pathways to slow disease progression is crucial in the treatment of IPF. Two antifibrotic medications, including pirfenidone and nintedanib, are Food and Drug Administration (FDA)-approved for treatment. ccf-DNA could become a new biomarker for IPF diagnosis to detect the disease at the early stage, while FDA-approved therapies could help to prevent late conditions from forming and decrease mortality rates.

PMID:40165930 | PMC:PMC11954786 | DOI:10.1007/s13205-025-04272-y

Clin Respir J. 2025 Apr;19(4):e70072. doi: 10.1111/crj.70072.

ABSTRACT

BACKGROUND: This study aims to summarize the similarities and differences in immune cell characteristics, and potential therapeutic targets between systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF).

METHODS: This study included SSc-ILD and SSc-nonILD patients who were admitted to Beijing Chaoyang Hospital between April 4th, 2013, to June 30th, 2023. Publicly available datasets, including peripheral blood monocular cell (pbmc) single-cell data, SSc, SSc-ILD pbmc transcriptome data, and SSc-ILD, IPF lung tissue transcriptome data were analyzed. Statistical analyses were conducted using the SPSS and R software, employing standard statistical methods and bioinformatics packages such as Seurat, DESeq2, enrichR, and CellChat.

RESULTS: The results revealed that the CD4+/CD8+ T cell ratio of pbmc in SSc-ILD patients was significantly higher than in SSc-nonILD patients. In IPF patients, an elevated CD4+/CD8+ T cell ratio was also observed in progressive group, and Treg and mature CD4+ T cells might cause this change. JAK-STAT pathway and the cytokine-cytokine receptor interaction pathway were activated in peripheral blood T cells of IPF patients. The CD30, CD40, and FLT3 signaling pathways were found to play crucial roles in T cell interactions with other immune cells among IPF patients. SPA17 as a commonly upregulated gene among SSc, SSc-ILD, and IPF pbmc and lung, with its expression correlating positively with disease severity and lung function progression.

CONCLUSION: CD4+/CD8+ T cell ratio might associate with ILD initiation and progression; Treg cells and mature CD4+ T cells play key roles of it. SPA17 might serve as a pan-ILD marker and associated with lung function progression.

PMID:40165483 | DOI:10.1111/crj.70072

J Gene Med. 2025 Apr;27(4):e70018. doi: 10.1002/jgm.70018.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an unknown etiology and complex pathophysiology that are not fully understood. The disease involves intricate cellular interplay, particularly among various immune cells. Currently, there is no treatment capable of reversing the fibrotic process or aiding lung regeneration. Hepatocyte growth factor (HGF) has demonstrated antifibrotic properties, whereas the adoptive transfer of modified T cells is a well-established treatment for various malignancies. We aimed to understand the dynamics of T cells in the progression of lung fibrosis and to study the therapeutic benefit of adoptive T cell transfer in a bleomycin-injured mouse lung (BLM) model.

METHODS: T cells were isolated from the spleen of naïve mice and transfected in vitro with mouse HGF plasmid and were administered intratracheally to the mice lungs 7 days post-bleomycin injury to the lung. Lung tissue and bronchoalveolar lavage were collected and analyzed using flow cytometry, histology, qRT-PCR, ELISA, and hydroxyproline assay.

RESULTS: Our findings demonstrate the successful T cell therapy of bleomycin-induced lung injury through the adoptive transfer of HGF-transfected T cells in mice. This treatment resulted in decreased collagen deposition and a balancing of immune cell exhaustion and cytokine homeostasis compared with untreated controls. In vitro testing showed enhanced apoptosis in myofibroblasts induced by HGF-overexpressing T cells.

CONCLUSIONS: Taken together, our data highlight the great potential of adoptive T cell transfer as an emerging therapy to counteract lung fibrosis.

PMID:40159455 | DOI:10.1002/jgm.70018