Biomed Rep. 2025 Jan 23;22(3):52. doi: 10.3892/br.2025.1930. eCollection 2025 Mar.

ABSTRACT

Metabolic disorders are a significant feature of fibrotic diseases. Nevertheless, the lack of sufficient proof regarding the cause-and-effect association between circulating metabolites and the promotion or prevention of idiopathic pulmonary fibrosis (IPF) persists. To assess the causal association between IPF and genetic proxies of 486 blood metabolites, a dual sample Mendelian randomization (MR) analysis was performed. Therefore, the two-sample MR technique and genome-wide association study data were employed to assess the association between 486 serum metabolites and IPF. To produce the primary outcomes, the inverse variance weighted (IVW) technique was applied, while to assess the stability and dependability of the outcomes, sensitivity analysis using MR-Egger analysis was performed. Additionally, weighted median, Cochran's Q-test, Egger intercept test and the leave-one-out method were used. The results of the present study revealed a total of 21 metabolites in blood circulation that could affect the risk of IPF (PIVW<0.05). Among them, 10 compounds were already known, namely cotinine [odds ratio (OR)=1.206; 95% confidence interval (CI), 1.002-1.452; P=0.047], hypoxanthine (OR=0.225; 95% CI, 0.056-0.899; P=0.034), aspartyl phenylalanine (OR=4.309; 95% CI, 1.084-17.131; P=0.038), acetyl-carnitine (OR=5.767; 95% CI, 1.398-23.789; P=0.015), 2-aminobutyrate (OR=0.155; 95% CI, 0.033-0.713; P=0.016), Docosapentaenoic acid (PubChem ID: 5497182; OR=0.214; 95% CI, 0.055-0.833; P=0.026), octanoyl-carnitine (PubChem ID: 177508; OR=3.398; 95% CI, 1.179-9.794; P=0.023), alpha-hydroxy-isovalerate (PubChem ID: 857803-94-2; OR=0.324; 95% CI, 0.112-0.931; P=0.036), 1,7-dimethylurate (PubChem ID: 91611; OR=0.401; 95% CI, 0.172-0.931; P=0.033) and 1-linoleoyl-glycerophosphocholine (PubChem ID: 657272; OR=6.559; 95% CI, 1.060-40.557; P=0.043). Additionally, the study also identified 11 currently unknown chemical structures. The results of Cochran's Q-test indicated that there was no significant heterogeneity, while MR-Egger's intercept analysis verified the lack of horizontal pleiotropy. The retention of one method for plotting also supported the reliability of the MR analysis. Overall, the results of the current study supported the cause-and-effect association between IPF and 21 blood metabolites, including 10 with already known chemical composition and 11 which are still awaiting determination. These findings could provide novel insights for the further investigation of the mechanism underlying the development of IPF.

PMID:39931651 | PMC:PMC11808644 | DOI:10.3892/br.2025.1930

F1000Res. 2024 Mar 22;13:216. doi: 10.12688/f1000research.142513.1. eCollection 2024.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with high mortality, and there are only two specific drugs available for therapeutic management with limitations. The study aims to identify comprehensive therapeutic mechanisms of Zingiber zerumbet rhizomes (ZZR) to treat IPF by using network pharmacology followed battery of in silico studies.

METHODS: The protein-protein interaction network was developed using Cytoscape to obtain core disease targets involved in IPF and their interactive molecules of ZZR. Based on the pharmacophore properties of phytomolecules from ZZR, the drug targets in IPF were explored. Protein-protein interaction network was built in Cytoscape to screen potential targets and components of ZZR. Molecular docking and dynamics were conducted as an empirical study to investigate the mechanism explored through network pharmacology in relation to the hub targets.

RESULTS: The network analysis conferred kaempferol derivatives that had demonstrated a promising therapeutic effect on the perturbed, robust network hubs of TGF-β1, EGFR, TNF-α, MMP2 & MMP9 reported to alter the biological process of mesenchymal transition, myofibroblast proliferation, and cellular matrix deposition in pulmonary fibrosis. The phytomolecules of ZZR act on two major significant pathways, namely the TGF-β-signaling pathway and the FOXO-signaling pathway, to inhibit IPF. Confirmational molecular docking and dynamics simulation studies possessed good stability and interactions of the protein-ligand complexes by RMSD, RMSF, rGyr, SASA, and principal component analysis (PCA). Validated molecular docking and dynamics simulations provided new insight into exploring the mechanism and multi-target effect of ZZR to treat pulmonary fibrosis by restoring the alveolar phenotype through cellular networking.

CONCLUSIONS: Network pharmacology and in silico studies confirm the multitargeted activity of ZZR in the treatment of IPF. Further in vitro and in vivo studies are to be conducted to validate these findings.

PMID:39931327 | PMC:PMC11809647 | DOI:10.12688/f1000research.142513.1

Med Adv. 2024 Dec;2(4):336-348. doi: 10.1002/med4.86. Epub 2024 Dec 17.

ABSTRACT

BACKGROUND: Accurate staging systems are essential for assessing the severity of idiopathic pulmonary fibrosis (IPF) and guiding clinical management. This study aimed to evaluate the prognostic value of pulmonary comorbidities and body mass index (BMI) in IPF, develop a nomogram predicting overall survival (OS), and create a nomogram-based survival prediction model.

METHODS: Patients with IPF were identified from electronic medical records of the West Virginia hospital system. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis was used for variable selection, and a nomogram was constructed. Risk groups were defined based on the nomogram's probability tertiles. The performance of the nomogram-based model was evaluated using Harrell's concordance index (C-index) and the Hosmer-Lemeshow test.

RESULTS: The study included 152 patients with IPF. The majority of the patients were elderly, male, and had a BMI above 24 kg/m2. The median survival duration was 7.6 years. The survival rates were 91% at 1 year, 78% at 3 years, and 68% at 5 years. LASSO regression selected carbon monoxide lung diffusion capacity percentage predicted (DLco%), BMI, pulmonary hypertension, pulmonary embolism, and sleep apnea as independent predictive variables. The nomogram demonstrated good discrimination (C-index = 0.71) and calibration.

CONCLUSIONS: Pulmonary comorbidities and BMI have significant prognostic value in IPF, emphasizing the necessity for consistent screening, assessment, and management of these factors in IPF care. Furthermore, the nomogram-based staging system showed promising performance in predicting OS and represents an actionable staging system that could potentially improve clinical management in IPF. Further validation of the nomogram is warranted to confirm its utility in clinical practice.

PMID:39931115 | PMC:PMC11809524 | DOI:10.1002/med4.86

J Cell Mol Med. 2025 Feb;29(3):e70402. doi: 10.1111/jcmm.70402.

ABSTRACT

The cell populations, particularly subpopulations, involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) remain incompletely understood. This study employed single-cell RNA-seq to identify cell populations and subpopulations with significantly altered proportions in the lungs of patients with IPF. In IPF lungs, endothelial cell proportions were significantly increased, while alveolar epithelial cell proportions were markedly decreased. Among the three identified fibroblast subpopulations, the proportion of myofibroblasts was significantly increased, while the proportions of the other two fibroblast subtypes were reduced. Similarly, within the three macrophage subpopulations, the macrophage_SPP1 subpopulation, localised to fibroblastic foci, showed a significant increase in proportion, while the alveolar macrophage subpopulation was significantly reduced. Trajectory analysis revealed that fibroblasts in IPF lungs could differentiate into myofibroblasts, and alveolar macrophages could transition into the macrophage_SPP1 subpopulation. Among T-cell subpopulations, only the CD4 T_FOXP3 subpopulation exhibited a significant change, whereas all four B-cell subpopulations showed significant proportional shifts. These findings provide a comprehensive view of the cellular alterations contributing to IPF pathogenesis. Extensive interactions among various cell populations and subpopulations were identified. The proportions of various cell populations and subpopulations in IPF lungs, including endothelial cells, fibroblasts, macrophages and B cells, were significantly altered. Further in-depth investigation into the roles of cell subpopulations with significantly altered proportions in the onset and progression of IPF will provide valuable insights into the pathological mechanisms underlying the disease. This understanding could facilitate the development of novel therapeutic strategies and medications for IPF treatment.

PMID:39928535 | DOI:10.1111/jcmm.70402

Am J Respir Crit Care Med. 2025 Feb 10. doi: 10.1164/rccm.202411-2157OC. Online ahead of print.

ABSTRACT

RATIONALE: Pulmonary hypertension (PH) commonly complicates idiopathic pulmonary fibrosis (IPF). However, the rate of change in pulmonary hemodynamics in IPF remains poorly defined.

OBJECTIVES: To examine the rate of change in pulmonary hemodynamics among patients with IPF.

METHODS: The rate of change in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) was examined in patients with IPF listed for lung transplantation. The 5th and 7th World Symposium on Pulmonary Hypertension definitions for precapillary PH were employed in this analysis.

MEASUREMENTS AND MAIN RESULTS: There were 496 patients with IPF that had at least two right heart catheterizations (RHCs) while listed for lung transplantation. The median time between repeated RHCs was 9 months (interquartile range [IQR]: 6-14). PH was present in 25.8% and 46.8% at the first RHC, while 42.9% and 64.3% had PH by the two definitions respectively, at the time of the final RHC. The median rate of change in the mPAP and PVR were 3.8 mmHg/year (IQR: -0.9-11.8) and 0.8 Wood Units/year (IQR: -0.2-2.4), respectively. The rate of PVR change was slower for those with established PH compared with those without PH. 28.6% of the patients had accelerated progression of their hemodynamics, arbitrarily defined as an increase in PVR of ≥ 2 Wood Units/year.

CONCLUSIONS: PH associated with IPF tends to progress in an unpredictable fashion, with some patients demonstrating an accelerated phenotype. Among patients with RHC hemodynamics below the threshold for therapy, close vigilance is warranted with consideration for an early repeat RHC. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:39928362 | DOI:10.1164/rccm.202411-2157OC

Brief Bioinform. 2024 Nov 22;26(1):bbaf033. doi: 10.1093/bib/bbaf033.

ABSTRACT

In single-cell studies, cells can be characterized with multiple sources of heterogeneity (SOH) such as cell type, developmental stage, cell cycle phase, activation state, and so on. In some studies, many nuisance SOH are of no interest, but may confound the identification of the SOH of interest, and thus affect the accurate annotate the corresponding cell subpopulations. In this paper, we develop B-Lightning, a novel and robust method designed to identify marker genes and cell subpopulations corresponding to an SOH (e.g. cell activation status), isolating it from other SOH (e.g. cell type, cell cycle phase). B-Lightning uses an iterative approach to enrich a small set of trustworthy marker genes to more reliable marker genes and boost the signals of the SOH of interest. Multiple numerical and experimental studies showed that B-Lightning outperforms existing methods in terms of sensitivity and robustness in identifying marker genes. Moreover, it increases the power to differentiate cell subpopulations of interest from other heterogeneous cohorts. B-Lightning successfully identified new senescence markers in ciliated cells from human idiopathic pulmonary fibrosis lung tissues, new T-cell memory and effector markers in the context of SARS-COV-2 infections, and their synchronized patterns that were previously neglected, new AD markers that can better differentiate AD severity, and new dendritic cell functioning markers with differential transcriptomics profiles across breast cancer subtypes. This paper highlights B-Lightning's potential as a powerful tool for single-cell data analysis, particularly in complex data sets where SOH of interest are entangled with numerous nuisance factors.

PMID:39927857 | DOI:10.1093/bib/bbaf033

JCI Insight. 2025 Feb 10;10(3):e165837. doi: 10.1172/jci.insight.165837.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes is significantly diminished in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2. Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.

PMID:39927460 | DOI:10.1172/jci.insight.165837

Health Sci Rep. 2025 Feb 6;8(2):e70328. doi: 10.1002/hsr2.70328. eCollection 2025 Feb.

ABSTRACT

BACKGROUND AND AIMS: Interactions between the lung microbiome and pulmonary epithelium plays a pivotal role in shaping immunity in the lung. Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease (ILD). Some patients with IPF develop episodic acute exacerbations often associated with microbial dysbiosis in the lungs. This study aimed to investigate etiologic agents as well as the lung microbiome in patients with ILDs and sarcoidosis.

METHODS: This study analyzed 31 patients divided into the IPF (IPF-stable, n = 12), acute exacerbation of ILDs (AE-ILDs, n = 6), and sarcoidosis (n = 13) groups. Bronchoalveolar lavage fluid (BALF) samples were analyzed by RNA-based metagenomic next-generation sequencing (NGS) on an Illumina platform.

RESULTS: In total, 87 pathogens were detected using metagenomic NGS at the genus level. Prevotella, Streptococcus, and Veillonella dominated the BALF microbial communities, and sequence reads of these bacteria were abundant, especially in the sarcoidosis group. Conversely, only a small number of bacterial reads were detected in the AE-ILDs group, and the overall proportion of microbial composition differed from that of the other groups. No significant difference was found in community diversity (α-diversity) among the groups, whereas the structural similarity of the microflora (β-diversity) differed significantly between the AE-ILDs and sarcoidosis groups.

CONCLUSIONS: Bacterial sequence reads in BALF were smaller in both the IPF-stable and AE-ILD groups than in the sarcoidosis group. Dysbiosis in the lung microbiome has been observed in patients with AE-ILD and may be related to the progression of inflammation.

PMID:39927182 | PMC:PMC11803077 | DOI:10.1002/hsr2.70328

Respir Med. 2025 Feb 5:107986. doi: 10.1016/j.rmed.2025.107986. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a distinctive chronic interstitial lung disease characterized by upper lobe-dominant elastofibrosis. Deepening of the suprasternal notch is a notable physical feature in patients with iPPFE. However, the anatomical explanation and clinical significance of iPPFE have not yet been studied in detail.

METHODS: We retrospectively examined 84 patients with iPPFE, 59 with idiopathic pulmonary fibrosis (IPF), 32 with chronic hypersensitivity pneumonitis (CHP), and 91 non-interstitial lung disease (ILD) controls. The depth of the suprasternal notch assessed on axial chest computed tomography and its association with clinical, radiological, and physiological parameters, and patient outcomes were investigated.

RESULTS: The depth of the suprasternal notch was anatomically correlated with the thickness of the pre-tracheal soft tissue and posterior or right deviation of the trachea in patients with iPPFE. The depth of the suprasternal notch effectively discriminated patients with iPPFE from those with IPF (sensitivity, 75%; specificity, 86.4%), CHP (sensitivity, 75%; specificity, 84.4%), and non-ILD controls (sensitivity, 75%; specificity, 83.5%), with a cutoff value of 9.5 mm. A log-rank test showed that patients with iPPFE with a deep suprasternal notch had significantly shorter survival than those without a deep suprasternal notch. In addition, a multivariate Cox regression analysis adjusted for age, sex, and %forced vital capacity showed that the depth of the suprasternal notch was an independent risk factor for mortality.

CONCLUSION: The suprasternal notch is a simple and useful indicator with diagnostic and prognostic implications for patients with iPPFE.

PMID:39921067 | DOI:10.1016/j.rmed.2025.107986

Cell Commun Signal. 2025 Feb 7;23(1):67. doi: 10.1186/s12964-025-02076-4.

ABSTRACT

Synchrotron-radiation nano-X-Ray Fluorescence (XRF) is a cutting-edge technique offering high-resolution insights into the elemental composition of biological tissues, shedding light on metabolic processes and element localization within cellular structures. In the context of Idiopathic Pulmonary Fibrosis (IPF), a debilitating lung condition associated with respiratory complications and reduced life expectancy, nano-XRF presents a promising avenue for understanding the disease's intricate pathology. Our developed workflow enables the assessment of elemental composition in both human and rodent fibrotic tissues, providing insights on the interplay between cellular compartments in chronic lung diseases. Our findings demonstrate trace element accumulations associated with anthracosis, a feature observed in IPF. Notably, Zn and Ca clusters approximately 750 nm in size were identified exclusively in IPF samples. While their specific role remains unclear, their presence may be associated with disease-specific processes. Additionally, we observed Fe and S signal colocalization in 650-nm structures within some IPF cells. Fe-S complexes in mitochondria are known to be associated with increased ROS production, suggesting a potential connection to the disease pathology. In contrast, a bleomycin-induced fibrosis rodent model exhibits a different elemental phenotype with low Fe and increased S, Zn, and Ca. Overall, our workflow highlights the effectiveness of synchrotron-based nano-XRF mapping in analyzing the spatial distribution of trace elements within diseased tissue, offering valuable insights into the elemental aspects of IPF and related chronic lung diseases.

PMID:39920750 | DOI:10.1186/s12964-025-02076-4

Cell Biol Toxicol. 2025 Feb 7;41(1):40. doi: 10.1007/s10565-025-09990-w.

ABSTRACT

Autophagy related genes (ATGs) play essential roles in maintaining cellular functions, although biological and pathological alterations of ATG phenotypes remain poorly understood. To address this knowledge gap, we utilized the single-cell sequencing technology to elucidate the transcriptomic atlas of ATGs in lung diseases, with a focus on lung epithelium and lymphocytes. This study conducted a comprehensive investigation into RNA profiles of ATGs in the lung tissues obtained from healthy subjects and patients with different lung diseases through single-cell RNA sequencing (scRNA-seq), including COVID-19 related acute lung damage, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), systemic sclerosis (SSC), and lung adenocarcinoma (LUAD). Our findings revealed significant variations of ATGs expression across lung epithelial cell subsets, e.g., over-expression of MAPK8 in basal cells, ATG10 in club cells, and BCL2 in a goblet cell subset. The changes of autophagy-related pathways varied between lung epithelial and lymphocyte subsets. We identified the disease-associated changes in ATG expression, including significant alterations in BCL2, BCL2L1, PRKCD, and PRKCQ in inflammatory lung diseases (COPD and IPF), and MAP2K7, MAPK3, and RHEB in lung cancer (LUAD), as compared to normal lung tissues. Key ligand-receptor pairs (e.g., CD6-ALCAM, CD99-CD99) and signaling pathways (e.g., APP, CD74) might serve as biomarkers for lung diseases. To evaluate ATGs responses to external challenges, we examined ATGs expression in different epithelial cell lines exposed to cigarette smoking extract (CSE), lysophosphatidylcholine (lysoPC), lipopolysaccharide (LPS), and cholesterol at various doses and durations. Notable changes were observed in CFLAR, EIF2S1, PPP2CA, and PPP2CB in A549 and H1299 against CSE and LPS. The heterogeneity of ATGs expression was dependent on cell subsets, pathologic conditions, and challenges, as well as varied among cellular phenotypes, functions, and behaviors, and the severity of lung diseases. In conclusion, our data might provide new insights into the roles of ATGs in epithelial biology and pulmonary disease pathogenesis, with implications for disease progression and prognosis.

PMID:39920481 | DOI:10.1007/s10565-025-09990-w

Respirology. 2025 Feb 7. doi: 10.1111/resp.14894. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a poor prognosis. Antifibrotics slow the decline of pulmonary function after 12-months, but limited studies have examined the role of circulatory biomarkers in antifibrotic treated IPF patients.

METHODS: Serum from 98 IPF participants, from the Australian Idiopathic Pulmonary Fibrosis Registry were collected at four time-points over 1 year post-antifibrotic treatment and analysed as two separate cohorts. Patients were stratified as progressive, if they experienced ≥ 10% decline in FVC or ≥ 15% decline in DLCO or were deceased within 1 year of treatment initiation: or otherwise as stable. Ten molecules of interest were measured by ELISAs in patient serum.

RESULTS: Baseline MMP7 levels were higher in progressive than stable patients in Cohort 1 (p = 0.02) and Cohort 2 (p = 0.0002). Baseline MMP7 levels also best differentiated progressive from stable patients (Cohort 1, AUC = 0.74, p = 0.02; Cohort 2, AUC = 0.81, p = 0.0003). Regression analysis of the combined cohort showed that elevated MMP7 levels predicted 12-month progression (OR = 1.530, p = 0.010) and increased risk of overall mortality (HR = 1.268, p = 0.002). LASSO regression identified a multi-biomarker panel (MMP7, ICAM-1, CHI3L1, CA125) that differentiated progression more accurately than MMP7 alone. Furthermore, GAP combined with MMP7, ICAM-1, CCL18 and SP-D was more predictive of 3-year mortality than GAP alone.

CONCLUSION: MMP7 along with a multi-biomarker and GAP panel can predict IPF progression and mortality, with the potential for optimising management.

PMID:39919729 | DOI:10.1111/resp.14894

PLoS One. 2025 Feb 7;20(2):e0318877. doi: 10.1371/journal.pone.0318877. eCollection 2025.

ABSTRACT

BACKGROUND: The therapeutic role of antifibrotic therapy has been well-established in idiopathic pulmonary fibrosis (IPF). However, its efficacy and safety for interstitial lung diseases (ILDs) other than IPF are not fully understood.

METHODS: We updated a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials and prospective studies on antifibrotic drug (nintedanib or pirfenidone) vs other intervention (placebo, no intervention or conventional treatment) in non-IPF ILDs. The primary outcomes were absolute change in forced vital capacity (FVC), all-cause mortality and serious adverse events (SAEs). The risk of bias was rated with the RoB2 tool and certainty of evidence was assessed by the GRADE approach.

RESULTS: 17 studies with 1908 patients were included. For the primary outcomes, pooled analyses of four trials with low risk of bias showed that antifibrotic drugs significantly ameliorated FVC decline (mean difference 86.21; 95% CI 49.38 to 123.03; I2 = 64%; TSA-adjusted CI 40.86 to 131.56). Based on five trials with low risk of bias, no difference was observed in all-cause mortality (RR 0.87; 95% CI 0.53 to 1.43; I2 = 0%; TSA-adjusted CI 0.12 to 6.53) and SAEs (RR 0.97; 95% CI 0.83 to 1.13; I2 = 0%; TSA-adjusted CI 0.74 to 1.28) between groups. However, based on two studies with 324 patients, benefit of antifibrotic drugs in FVC was not shown in the subgroup taking mycophenolate (mean difference 17.08; 95% CI -56.22 to 90.37), which also had higher risk of SAEs (RR 1.71; 95% CI 1.09 to 2.70), although both were contested by TSA.

CONCLUSION: Our study suggests that antifibrotic drugs are beneficial for patients with non-IPF ILDs in slowing disease progression, whereas may not correlate to all-cause mortality and SAEs. However, for patients taking mycophenolate, antifibrotic drugs may do more harm than good. More investigations are warranted to validate current findings.

PMID:39919132 | DOI:10.1371/journal.pone.0318877

Cell Rep. 2025 Feb 6;44(2):115275. doi: 10.1016/j.celrep.2025.115275. Online ahead of print.

ABSTRACT

Mucosal-associated invariant T (MAIT) cells, the most abundant unconventional T cells in the lung, can exhibit a wide range of functional responses to different triggers via their T cell receptor (TCR) and/or cytokines. Their role, especially in sterile lung injury, is unknown. Using single-cell RNA sequencing (scRNA-seq), spectral analysis, and adoptive transfer in a bleomycin-induced sterile lung injury, we found that bleomycin activates murine pulmonary MAIT cells and is associated with a protective role against bleomycin-induced lung injury. MAIT cells drive the accumulation of type 1 conventional dendritic cells (cDC1s), limiting tissue damage in a DNGR-1-dependent manner. Human scRNA-seq data revealed that MAIT cells were activated, with increased cDC populations in idiopathic pulmonary fibrosis patients. Thus, MAIT cells enhance defense against sterile lung injury by fostering cDC1-driven anti-fibrotic pathways.

PMID:39918959 | DOI:10.1016/j.celrep.2025.115275

Expert Rev Respir Med. 2025 Feb 7. doi: 10.1080/17476348.2025.2464886. Online ahead of print.

NO ABSTRACT

PMID:39917880 | DOI:10.1080/17476348.2025.2464886

Epigenetics. 2025 Dec;20(1):2462898. doi: 10.1080/15592294.2025.2462898. Epub 2025 Feb 7.

ABSTRACT

Although N6-methyladenosine (m6A) may be related to the pathogenesis of fibrotic process, the mechanism of m6A modification in aging-related idiopathic pulmonary fibrosis (IPF) remains unclear. Three-milliliter venous blood was collected from IPF patients and healthy controls. MeRIP-seq and RNA-seq were utilized to investigate differential m6A modification. The expressions of identified m6A regulator and target gene were validated using MeRIP-qPCR and real-time PCR. Moreover, we established an animal model and a senescent model of A549 cells to explore the associated molecular mechanism. Our study provided a panorama of m6A methylation in IPF. Increased peaks (3756) and decreased peaks (4712) were observed in the IPF group. The association analysis showed that 749 DEGs were affected by m6A methylation in IPF. Among the m6A regulators, the expression of METTL14 decreased in IPF. The m6A level of our interested gene DDIT4 decreased significantly, but the mRNA level of DDIT4 was higher in IPF. This was further verified in bleomycin-induced pulmonary fibrosis. At the cellular level, it was further confirmed that METTL14 and DDIT4 might participate in the senescence of alveolar epithelial cells. The downregulation of METTL14 might inhibit the decay of DDIT4 mRNA by reducing the m6A modification level of DDIT4 mRNA, leading to high expression of DDIT4 mRNA and protein. Our study provided a panorama of m6A alterations in IPF and discovered METTL14 as a potential intervention target for epigenetic modification in IPF. These results pave the way for future investigations regarding m6A modifications in aging-related IPF.

PMID:39916577 | DOI:10.1080/15592294.2025.2462898

Expert Opin Investig Drugs. 2025 Feb 6. doi: 10.1080/13543784.2025.2462592. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease of unknown cause that occurs primarily in older adults and is associated with poor quality of life and substantial healthcare utilization. IPF has a dismal prognosis. Indeed, first-line therapy, which includes nintedanib and pirfenidone, does not stop disease progression and is often associated with tolerability issues. Therefore, there remains a high medical need for more efficacious and better tolerated treatments.

AREAS COVERED: Gene therapy is a relatively unexplored field of research in IPF that has the potential to mitigate a range of profibrotic pathways by introducing genetic material into cells. Here, we summarize and critically discuss publications that have explored the safety and efficacy of gene therapy in experimentally-induced pulmonary fibrosis in animals, as clinical studies in humans have not been published yet.

EXPERT OPINION: The application of gene therapy in pulmonary fibrosis requires further investigation to address several technical and biological hurdles, improve vectors' design, drug delivery, and target selection, mitigate off-target effects and develop markers of gene penetration into target cells. Long-term clinical data are needed to bring gene therapy in IPF one step closer to practice.

PMID:39916340 | DOI:10.1080/13543784.2025.2462592

Biofabrication. 2025 Feb 6. doi: 10.1088/1758-5090/adb338. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. Macrophages are implicated in the fibrotic process, but exhibit remarkable plasticity in the activated immune environment in vivo, presenting significant challenges as therapeutic targets. To explore the influence of macrophages on IPF and develop macrophage-targeted therapies, we engineered a micro-lung chip with a lung epithelium-interstitium tissue unit to establish a controlled immune environment containing only macrophages. We discovered that macrophages exacerbated inflammation and fibrosis by comparing microchips treated with bleomycin in the presence and absence of macrophages. Based on the duration of bleomycin treatment, we established pathological models corresponding to inflammation and fibrosis stages. Transcriptome analysis revealed that activation of the PI3K-AKT signaling pathway facilitates the transition from inflammation to fibrosis. However, LY294002, a PI3K inhibitor, not only suppressed fibrosis and decreased the accumulation of M2 macrophages but also intensified the severity of inflammation. These findings suggest that macrophages play a pivotal role in the potential development at the tissue level. The micro-lung chip cocultured with macrophages holds significant potential for exploring the pathological progression of IPF and elucidating the mechanisms of anti-fibrotic drugs.

PMID:39914008 | DOI:10.1088/1758-5090/adb338

Expert Rev Respir Med. 2025 Feb 6. doi: 10.1080/17476348.2025.2464035. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive scarring and reduced survival. The development of IPF is influenced by rare and common genetic variants, cigarette smoking, aging, and environmental exposures. Among the two dozen genetic contributors, the MUC5B promoter variant (rs35705950) is the dominant risk factor, increasing the risk of both familial and sporadic IPF and accounting for nearly 50% of the genetic predisposition to the disease.

AREAS COVERED: This review provides an expert perspective on the genetic underpinnings of IPF rather than a systematic analysis, emphasizing key insights into its genetic basis. The articles referenced in this review were identified through targeted searches in PubMed, Scopus, and Web of Science for studies published between 2000 and 2023, prioritizing influential research on the genetic factors contributing to IPF. Search terms included 'idiopathic pulmonary fibrosis,' 'genetics,' 'MUC5B,' 'telomere dysfunction,' and 'surfactant proteins.' The selection of studies was guided by the authors' expertise, focusing on the most relevant publications.

EXPERT OPINION: The identification of genetic variants not only highlights the complexity of IPF but also offers potential for earlier diagnosis and personalized treatment strategies targeting specific genetic pathways, ultimately aiming to improve patient outcomes.

PMID:39912527 | DOI:10.1080/17476348.2025.2464035

J Med Chem. 2025 Feb 5. doi: 10.1021/acs.jmedchem.5c00263. Online ahead of print.

ABSTRACT

Despite significant advancements in the treatment options for idiopathic pulmonary fibrosis (IPF), the disease remains aggressive and incurable. This viewpoint summarizes the discovery of a neutral, potent, and selective lysophosphatidic acid receptor 1 antagonist for the treatment of IPF. The lead optimization without the cocrystal structure guidance is worth it to highlight.

PMID:39909836 | DOI:10.1021/acs.jmedchem.5c00263