Cureus. 2025 Jan 16;17(1):e77522. doi: 10.7759/cureus.77522. eCollection 2025 Jan.

ABSTRACT

Bird fancier's lung (BFL) is a subtype of hypersensitivity pneumonitis (HP), an immune-mediated interstitial lung disease (ILD) resulting from the repeated inhalation of avian proteins found in bird droppings, feathers, and serum. Diagnosing BFL is challenging due to nonspecific symptoms that overlap with other ILDs like idiopathic pulmonary fibrosis and sarcoidosis. This complexity is heightened during pandemics such as coronavirus disease 2019 (COVID-19), where respiratory symptoms may be misattributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, leading to diagnostic anchoring and delays in appropriate management. High-resolution computed tomography (HRCT) is pivotal in detecting subtle pulmonary changes, characteristic of HP, surpassing standard chest radiographs. We present the case of a 43-year-old male pigeon keeper with an eight-week history of progressive dyspnea on exertion and intermittent chest pain. Despite unremarkable chest X-rays, HRCT revealed bilateral diffuse centrilobular nodules, patchy ground-glass opacities, and a mosaic attenuation pattern without fibrosis, consistent with acute HP. A thorough occupational history uncovered significant avian antigen exposure, and a family history suggested genetic susceptibility. The patient was diagnosed with BFL and treated with a tapering regimen of oral corticosteroids, starting at 40 mg/day. He was advised to cease pigeon keeping and avoid future avian exposure. Significant symptomatic improvement occurred within three months. Follow-up imaging over one year confirmed stable lung parenchyma with no disease progression or recurrence. This case underscores the importance of incorporating detailed occupational histories and utilizing advanced imaging modalities like HRCT when standard imaging is inconclusive. Early identification and intervention are crucial to prevent progression to chronic HP and irreversible fibrosis. Management should focus on reducing inflammation with corticosteroids and implementing strict environmental controls to prevent re-exposure. Long-term follow-up is essential to monitor for recurrence and maintain remission. Clinicians should remain vigilant for alternative diagnoses during pandemics to avoid diagnostic anchoring. This case contributes to the evidence supporting HRCT's critical role in early HP detection and emphasizes heightened clinical awareness of occupational lung diseases. A multidisciplinary approach involving pulmonologists, radiologists, and occupational medicine specialists is key to optimizing outcomes in HP and other ILDs.

PMID:39958101 | PMC:PMC11830419 | DOI:10.7759/cureus.77522

Biomed Pharmacother. 2025 Feb 15;184:117891. doi: 10.1016/j.biopha.2025.117891. Online ahead of print.

ABSTRACT

Cyclin-dependent kinase 8 (CDK8) plays a crucial role in the transforming growth factor beta (TGF-β) signaling pathway, which is critical to the pathology of idiopathic pulmonary fibrosis (IPF). CDK8 promotes the epithelial-mesenchymal transition (EMT) and excessive extracellular matrix (ECM) deposition, making it a promising target for IPF treatment. This study focused on optimizing F059-1017, a previously identified CDK8 inhibitor, to enhance its potency. Through integrated structure-based modifications, a series of compounds was synthesized, and their inhibitory effects on CDK8 were tested. Results indicated that substituting with cyclopentanone significantly improved the inhibitory activity, and compound 4j demonstrated the best potency (IC50 = 16 nM). Notably, compared to F059-1017, its potency increased 35-fold, and kinase profiling revealed that the compound was selective for CDK8. Compound 4j inhibited the TGF-β1-induced EMT, cell migration, and morphological changes in A549 cells at a concentration of 0.1 μM and inhibited ECM and EMT protein expressions. In addition, the compound blocked TGF-β1-induced transcriptional changes and inhibited Smad3 and RNA polymerase II phosphorylation. These results highlight the potential of the optimized CDK8 inhibitor as a prospective drug for IPF treatment.

PMID:39955852 | DOI:10.1016/j.biopha.2025.117891

Eur J Pharmacol. 2025 Feb 13:177381. doi: 10.1016/j.ejphar.2025.177381. Online ahead of print.

ABSTRACT

Bicyclol, a drug stemmed from the traditional Chinese medicine Schisandra chinensis, has been widely utilized in clinical practice due to its efficacy and safety to manage hepatopathy. Its diverse biological properties-including antiviral, anti-inflammatory, antifibrotic, immunomodulatory, antioxidative, antisteatotic, and antitumor effects-underscore its significant medicinal effects in versatile hepatic disorders, incorporating viral hepatitis, non-alcoholic fatty liver disease, hepatocellular carcinoma, acute hepatic failure, hepatic fibrosis as well as drug-induced liver injury. Furthermore, ongoing researches into the molecular mechanisms, biological activities and mode of actions concerning bicyclol have uncovered its potential therapeutic implications in other multiple diseases/conditions. Studies have indicated promising efficacy pertaining to bicyclol to treat idiopathic pulmonary fibrosis, acute lung injury, cerebral ischemia/reperfusion injury, renal dysfunction, renal cell carcinoma, and cardiovascular diseases. Accordingly, this narrative review article summarizes the current understanding of diverse biological activities and underpinning mechanisms of bicyclol across a range of diseases, as well as its pharmacokinetics, toxicity profile and shed light on future perspectives.

PMID:39954842 | DOI:10.1016/j.ejphar.2025.177381

Transl Res. 2025 Feb 12:S1931-5244(25)00023-4. doi: 10.1016/j.trsl.2025.02.002. Online ahead of print.

ABSTRACT

Mitochondrial dysfunction is closely associated with idiopathic pulmonary fibrosis (IPF). However, the causal association between mitochondria-related genes and IPF remains to be determined. We obtained gene expression, protein abundance, and methylation quantitative trait locus data for mitochondria-related genes from previous studies. Genome-wide association study data for patients with IPF were obtained from the FinnGen study. A two-sample Mendelian randomisation analysis was conducted to assess the association between mitochondria-related genes and IPF. Furthermore, we conducted validation of expression differences utilizing transcriptome data derived from the BLM-induced pulmonary fibrosis mouse model (n=15). Concurrently, multiphoton imaging was utilized to quantify collagen contents and structural assessment. The direction of causality was verified using the Steiger test, and colocalisation analysis was used to better validate causality. Single-cell data were used to explore the localisation and expression of positive genes across different cell types. The study identified significant associations between mitochondria-related genes and IPF, with POLG and NDUFB10 classified as Grade 1; LYRM4, NBR1, and ACSF3 as Grade 2; MCL1, GFER, MFN2, IVD, and SLC25A35 as Grade 3; and METAP1D and MTX1 as Grade 4. Single-cell analysis showed elevated expression of NBR1, MCL1, and MTX1 in pulmonary myofibroblasts of IPF. This study elucidated the causal effects of mitochondria-related genes on IPF, underscoring their significance in pathogenesis. These findings contribute to an improved understanding of the mechanisms underlying IPF, offering new potential therapeutic targets for interventions.

PMID:39952317 | DOI:10.1016/j.trsl.2025.02.002

Aging Cell. 2025 Feb 13:e14503. doi: 10.1111/acel.14503. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-associated disease characterized by the irreversible accumulation of excessive extracellular matrix components by activated myofibroblasts (aMYFs). Following bleomycin administration in young mice, fibrosis formation associated with efficient resolution takes place limiting the clinical relevance of this model for IPF. In this study, we used aged mice in combination with bleomycin administration to trigger enhanced fibrosis formation and delayed resolution as a more relevant model for IPF. Alveolosphere assays were carried out to compare the alveolar resident mesenchymal niche activity for AT2 stem cells in young versus old mice. Lineage tracing of the Acta2+ aMYFs in old mice exposed to bleomycin followed by scRNAseq of the lineage-traced cells isolated during fibrosis formation and resolution was performed to delineate the heterogeneity of aMYFs during fibrosis formation and their fate during resolution. Integration of previously published similar scRNAseq results using young mice was carried out. Our results show that alveolar resident mesenchymal cells from old mice display decreased supporting activity for AT2 stem cells. Our findings suggest that the cellular and molecular mechanisms underlying the aMYFs formation and differentiation towards the Lipofibroblast phenotype are mostly conserved between young and old mice. In addition to persistent fibrotic signaling in aMYF from old mice during resolution, we also identified differences linked to interleukin signaling in old versus young alveolar fibroblast populations before and during bleomycin injury. Importantly, our work confirms the relevance of a subcluster of aMYFs in old mice that is potentially relevant for future management of IPF.

PMID:39945330 | DOI:10.1111/acel.14503

Front Genet. 2025 Jan 29;15:1496462. doi: 10.3389/fgene.2024.1496462. eCollection 2024.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a rare but debilitating lung disease characterized by excessive fibrotic tissue accumulation, primarily affecting individuals over 50 years of age. Early diagnosis is challenging, and without intervention, the prognosis remains poor. Understanding the molecular mechanisms underlying IPF pathogenesis is crucial for identifying diagnostic markers and therapeutic targets.

METHODS: We analyzed transcriptomic data from lung tissues of IPF patients using two independent datasets. Differentially expressed genes (DEGs) were identified, and their functional roles were assessed through pathway enrichment and tissue-specific expression analysis. Protein-protein interaction (PPI) networks and co-expression modules were constructed to identify hub genes and their associations with disease severity. Machine learning approaches were applied to identify genes capable of differentiating IPF patients from healthy individuals. Regulatory signatures, including transcription factor and microRNA interactions, were also explored, alongside the identification of potential drug targets.

RESULTS: A total of 275 and 167 DEGs were identified across two datasets, with 67 DEGs common to both. These genes exhibited distinct expression patterns across tissues and were associated with pathways such as extracellular matrix organization, collagen fibril formation, and cell adhesion. Co-expression analysis revealed DEG modules correlated with varying IPF severity phenotypes. Machine learning analysis pinpointed a subset of genes with high discriminatory power between IPF and healthy individuals. PPI network analysis identified hub proteins involved in key biological processes, while functional enrichment reinforced their roles in extracellular matrix regulation. Regulatory analysis highlighted interactions with transcription factors and microRNAs, suggesting potential mechanisms driving IPF pathogenesis. Potential drug targets among the DEGs were also identified.

DISCUSSION: This study provides a comprehensive transcriptomic overview of IPF, uncovering DEGs, hub proteins, and regulatory signatures implicated in disease progression. Validation in independent datasets confirmed the relevance of these findings. The insights gained here lay the groundwork for developing diagnostic tools and novel therapeutic strategies for IPF.

PMID:39944354 | PMC:PMC11813903 | DOI:10.3389/fgene.2024.1496462

Expert Rev Respir Med. 2025 Feb 13. doi: 10.1080/17476348.2025.2467341. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) isa chronic, progressive lung disease characterized by distorted alveolar structureand reduced lung compliance, and impaired ventilation-perfusion. Small airwaydisease (SAD) is often termed a 'quietzone' due to its asymptomatic nature. Around 30-40% of IPF patients exhibit SAD,which is associated with worse prognosis, higher fibrosis and emphysema scores,and elevated mortality risk. We used PubMed and Google Scholar for literaturesearch.

AREAS COVERED: This review explores thepathophysiology of small airways in IPF, focusing on 1. risk factors, includingage, gender, smoking and occupational dust exposure, and ozone. 2. Diagnosticchallenges: SAD is difficult to detect through traditional spirometry or high-resolutioncomputed tomography imaging due to resolutionlimitations. 3. Early physiologicalchanges of small airways include airway wall thickening, lumen distortion, andreduced terminal bronchioles, preceding microscopic fibrosis, occurs in the earlyprocess of IPF. 4. Pathological mechanisms: The review examines the underlyingmechanisms driving small airway disease in IPF.

EXPERT OPINION: A comprehensive approach is essential to improve the understanding andmanagement of SAD in IPF. Priorities include identifying therapeutic targets,advanced imaging and functional assessments. Forced oscillation technique should be introduced for early detection for smallairway abnormalities in IPF.

PMID:39943815 | DOI:10.1080/17476348.2025.2467341

J Clin Med. 2025 Jan 23;14(3):731. doi: 10.3390/jcm14030731.

ABSTRACT

Background: Transbronchial lung cryobiopsy (TBLC) has a high incidence of adverse events. This study aimed to investigate the relationship between the occurrence of these events and the condition of the pathology samples or pathological diagnosis in TBLC. Methods: We studied 102 patients who underwent TBLC for the diagnosis of interstitial lung disease. We analyzed the association between the condition or diagnosis of pathology samples and the occurrence of TBLC-related adverse events, including hemorrhage, pneumothorax, and acute exacerbation of interstitial lung disease. Results: The adverse events occurred in 19 patients (18.6%), of which hemorrhage was the most common (14 patients, 13.7%). The patients who experienced adverse events, especially hemorrhage, were less likely to have successful sampling with TBLC and showed lower diagnostic confidence in the pathology results. The diagnostic confidence was level A in 50 cases (49.0%) and level C in 23 cases (22.6%). TBLC-related adverse events, including hemorrhage, were significantly more common in patients with lower pathological confidence levels. Conclusions: TBLC-related adverse events, particularly hemorrhage, can lead to fewer successful samples and lower levels of diagnostic confidence.

PMID:39941401 | DOI:10.3390/jcm14030731

J Clin Med. 2025 Jan 22;14(3):714. doi: 10.3390/jcm14030714.

ABSTRACT

Background: Over the last few years, a few imaging studies have performed conventional transthoracic echocardiography (TTE) implemented with speckle tracking echocardiography (STE) for the assessment of biventricular mechanics in patients with non-advanced idiopathic pulmonary fibrosis (IPF). This systematic review and meta-analysis aimed at evaluating the overall effect of mild-to-moderate IPF on the main indices of biventricular systolic function assessed by TTE and STE. Methods: All imaging studies assessing right ventricular (RV)-global longitudinal strain (GLS), left ventricular (LV)-GLS, tricuspid annular plane systolic excursion (TAPSE), and left ventricular ejection fraction (LVEF) in IPF patients vs. healthy controls, selected from PubMed, Scopus, and EMBASE databases, were included. Continuous data (RV-GLS, LV-GLS, TAPSE, and LVEF) were pooled as standardized mean differences (SMDs) comparing the IPF group with healthy controls. The SMD of RV-GLS was calculated using the random-effect model, whereas the SMDs of LV-GLS, TAPSE, and LVEF were calculated using the fixed-effect model. Results: The full texts of 6 studies with 255 IPF patients and 195 healthy controls were analyzed. Despite preserved TAPSE and LVEF, both RV-GLS and LV-GLS were significantly, although modestly, reduced in the IPF patients vs. the controls. The SMD was large (-1.01, 95% CI -1.47, -0.54, p < 0.001) for RV-GLS, medium (-0.62, 95% CI -0.82, -0.42, p < 0.001) for LV-GLS, small (-0.42, 95% CI -0.61, -0.23, p < 0.001) for TAPSE, and small and not statistically significant (-0.20, 95% CI -0.42, 0.03, p = 0.09) for LVEF assessment. Between-study heterogeneity was high for the studies assessing RV-GLS (I2 = 80.5%), low-to-moderate for those evaluating LV-GLS (I2 = 41.7%), and low for those measuring TAPSE (I2 = 16.4%) and LVEF (I2 = 7.63%). The Egger's test yielded a p-value of 0.60, 0.11, 0.31, and 0.68 for the RV-GLS, LV-GLS, TAPSE, and LVEF assessment, respectively, indicating no publication bias. On meta-regression analysis, none of the moderators was significantly associated with effect modification for RV-GLS (all p > 0.05). The sensitivity analysis supported the robustness of the results. Conclusions: RV-GLS impairment is an early marker of subclinical myocardial dysfunction in mild-to-moderate IPF. STE should be considered for implementation in clinical practice for early detection of RV dysfunction in IPF patients without advanced lung disease.

PMID:39941384 | DOI:10.3390/jcm14030714

Int J Mol Sci. 2025 Feb 6;26(3):1378. doi: 10.3390/ijms26031378.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has been associated with mitochondrial dysfunction. We investigated whether mitochondrial DNA variants in peripheral blood leukocytes (PBLs), which affect proteins of the respiratory chain and mitochondrial function, could be associated with an increased risk and poor prognosis of IPF. From 2020 to 2022, we recruited 36 patients (age: 75.3 ± 8.5; female: 19%) with IPF, and 80 control subjects (age: 72.3 ± 9.0; female: 27%). The mitochondrial genome of peripheral blood leukocytes was determined using next-generation sequencing. During a 45-month follow-up, 10 (28%) patients with IPF remained stable and the other 26 (72%) progressed, with 12 (33%) mortalities. IPF patients had more non-synonymous (NS) variants (substitution/deletion/insertion) in mitochondrial COX3 gene (coding for subunit 3 of complex IV of the respiratory chain), and more mitochondrial tRNA variants located in the anticodon (AC) stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure in PBLs than the control group. The succumbed IPF patients were older, had lower initial diffusion capacity, and higher initial fibrosis score on high-resolution computerized tomography (HRCT) than the alive group. NS variants in mitochondrial COX3 gene and tRNA variants in PBLs were associated with shorter survival. Our study shows that (1) leukocyte mitochondrial COX3 NS variants are associated with risk and prognosis of IPF; (2) leukocyte mitochondrial tRNA variants located in the AC stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure are associated with risk, and the presence of tRNA variants is associated with poor prognosis of IPF.

PMID:39941146 | DOI:10.3390/ijms26031378

ACS Appl Mater Interfaces. 2025 Feb 12. doi: 10.1021/acsami.4c21657. Online ahead of print.

ABSTRACT

Biodegradable poly(β-amino) esters (PBAEs) have been a focus of interest for delivering therapeutic siRNA for several years. While no approved therapies are on the market yet, our study aims to advance PBAE-based treatments for currently "undruggable" diseases. The PBAEs used in this study are based on a recently reported step-growth copolymerization, which results in polymers with a unique balance of lipophilicity and positive charge, thereby showcasing diverse properties. Upon incubation with siRNA, these PBAEs form a unique structure and topology, which we classify as a subtype of classical polyplex, termed "micelle-embedded polyplexes" (mPolyplexes). The impact of different nebulizers on the physicochemical performance of these nanoparticles was investigated, and it was found that various mPolyplexes can be nebulized using vibrating-mesh nebulizers without the loss of gene silencing activity nor a change in physicochemical properties, setting them apart from other nanoparticles such as marketed LNPs. Finally, their therapeutic application was tested ex vivo in human precision-cut lung slices from patients with lung fibrosis. mPolyplexes mediated 52% gene silencing of matrix metalloprotease 7 (MMP7) and a downstream effect on collagen I (Col I) with 33% downregulation as determined via qPCR.

PMID:39938880 | DOI:10.1021/acsami.4c21657

J Proteomics. 2025 Feb 10:105400. doi: 10.1016/j.jprot.2025.105400. Online ahead of print.

NO ABSTRACT

PMID:39938635 | DOI:10.1016/j.jprot.2025.105400

Respir Investig. 2025 Feb 11;63(3):241-246. doi: 10.1016/j.resinv.2025.01.008. Online ahead of print.

ABSTRACT

BACKGROUND: The 6-min walk test (6MWT), used to monitor disease progression or exacerbation in interstitial lung disease, faces challenges such as requiring a 30-m walking path and difficulty assessing patients with gait disturbance. The 1-min sit-to-stand test (1STST) offers a convenient alternative, potentially addressing these issues. Despite its advantages, the effectiveness of the 1STST in patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) still needs to be explored. We assessed 1STST's ability to detect exercise-induced desaturation in a randomized, crossover trial involving patients with IPF or PPF.

METHODS: Participants were divided into group A (6MWT to 1STST) and B (1STST to 6MWT), with a 30-min rest period between the tests. The primary endpoint was the difference in nadir oxygen saturation (SpO2) between the groups throughout the study. Secondary endpoints included the percentage of participants with a nadir SpO₂ <88% during the tests, a decline of ≥4% in SpO2, and the variation in Borg scores post-tests.

RESULTS: Twenty-three participants (91.3% male; mean age ± standard deviation: 77.2 ± 7.4 years) diagnosed with IPF and PPF were enrolled in this study. The difference in nadir SpO2 between the 1STST and 6MWT was 1.14% (95% confidence interval: -0.18, 2.48), with the 95% confidence intervals falling within the predefined equivalence range. No significant differences were observed in the secondary endpoints.

CONCLUSIONS: The results suggest that the 1STST is as effective as the 6MWT in detecting desaturation in patients with IPF and PPF.

TRIAL REGISTRATION: This study was registered on the website of the Japan Registry of Clinical Trials (jRCT1032230037; URL: https://jrct.niph.go.jp/).

PMID:39938407 | DOI:10.1016/j.resinv.2025.01.008

Ann Am Thorac Soc. 2025 Feb 12. doi: 10.1513/AnnalsATS.202501-130ED. Online ahead of print.

NO ABSTRACT

PMID:39938064 | DOI:10.1513/AnnalsATS.202501-130ED

J Surg Res. 2025 Jan;305:295-303. doi: 10.1016/j.jss.2024.11.002. Epub 2024 Dec 27.

ABSTRACT

INTRODUCTION: Due to parenchymal fibrosis and chest wall contraction in idiopathic pulmonary fibrosis (IPF), donor lung allografts are generally undersized to accommodate smaller diseased chest cavities. We hypothesized that transplanting oversized allografts (OAs) in recipients with IPF would be associated with thoracic cavity expansion.

METHODS: A single center retrospective study of IPF patients who underwent lung transplant between 2014 and 2022 was conducted. Size matching was determined by comparing donor and recipient lung height on chest radiographs, measured from lung apex to middiaphragm on donor and recipient inspiratory anterior to posterior chest radiographs. Allografts that were ≥10% larger on chest radiograph compared to corresponding recipient lungs were deemed OAs, or not oversized allografts. Allograft lung height and pulmonary function tests were collected at 1, 6, and 12 mo and a comparative analysis was performed.

RESULTS: The OA group had a significant increase in change of height in the left lung at 1 mo and both lungs at 6 mo (P < 0.05). There were no significant differences in change of forced expiratory volume in 1 s at 1, 6, 12 mo between the two groups. The change in forced vital capacity was significantly increased in the OA group at 6 mo (P < 0.05). The degree of donor to recipient allograft size mismatch and resultant recipient pleural cavity expansion was significantly correlated at 1 and 6 mo (P < 0.05).

CONCLUSIONS: Transplanting larger allografts into IPF patients was associated with pleural cavity expansion, without an associated change in pulmonary function tests. Thus, larger allografts potentially can be used in IPF patients, thereby increasing donor availability for these patients.

PMID:39937562 | DOI:10.1016/j.jss.2024.11.002

Cells. 2025 Feb 5;14(3):222. doi: 10.3390/cells14030222.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is an epithelial-driven interstitial lung disease of unknown etiology characterized by the excessive proliferation of fibroblast populations that synthesize large amounts of extracellular matrix. In this devastating disorder, all aging hallmarks appear prematurely or are altered. This review highlights key findings about IPF characteristics recently recognized as hallmarks of aging, including mechanical alterations, inflammaging, dysbiosis, alternative splicing, and disabled macroautophagy. It also revisits the classic hallmarks of aging, which encompass stem cell exhaustion, cellular senescence, and altered intercellular communication. Enhancing our understanding of the fundamental processes that underlie the altered hallmarks of aging in IPF may facilitate the development of innovative experimental strategies to improve therapeutic outcomes.

PMID:39937013 | DOI:10.3390/cells14030222

Front Genet. 2025 Jan 22;15:1464471. doi: 10.3389/fgene.2024.1464471. eCollection 2024.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a severe chronic respiratory disease characterized by treatment challenges and poor prognosis. Identifying relevant biomarkers for effective early-stage risk prediction is therefore of critical importance.

METHODS: In this study, we obtained gene expression profiles and corresponding clinical data of IPF patients from the GEO database. GO enrichment and KEGG pathway analyses were performed using R software. To construct an IPF risk prediction model, we employed LASSO-Cox regression analysis and the SVM-RFE algorithm. PODNL1 and PIGA were identified as potential biomarkers associated with IPF onset, and their predictive accuracy was confirmed using ROC curve analysis in the test set. Furthermore, GSEA revealed enrichment in multiple pathways, while immune function analysis demonstrated a significant correlation between IPF onset and immune cell infiltration. Finally, the roles of PODNL1 and PIGA as biomarkers were validated through in vivo and in vitro experiments using qRT-PCR, Western blotting, and immunohistochemistry.

RESULTS: These findings suggest that PODNL1 and PIGA may serve as critical biomarkers for IPF onset and contribute to its pathogenesis.

DISCUSSION: This study highlights their potential for early biomarker discovery and risk prediction in IPF, offering insights into disease mechanisms and diagnostic strategies.

PMID:39935693 | PMC:PMC11811625 | DOI:10.3389/fgene.2024.1464471

J Inflamm Res. 2025 Feb 7;18:1899-1910. doi: 10.2147/JIR.S499029. eCollection 2025.

ABSTRACT

While TRIM proteins are extensively studied in the context of lung tumors, their roles in non-tumor chronic lung diseases remain underexplored. This review delves into the emerging significance of TRIM family proteins in the pathogenesis of idiopathic pulmonary fibrosis (IPF), asthma, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension (PH). TRIM proteins modulate key pathological processes, including inflammation, fibrosis, and cellular remodeling, contributing to disease progression. We highlight their potential as biomarkers and therapeutic targets, offering promising avenues for drug development in these debilitating respiratory disorders. However, the translation of these findings into clinical applications faces significant challenges. These include the dual functional nature of TRIM proteins, their context-dependent roles, the complexity of their downstream signaling networks, and the limitations of current therapeutic strategies in achieving tissue-specific targeting with minimal off-target effects. Addressing these challenges will require innovative approaches and interdisciplinary efforts to unlock the therapeutic potential of TRIM proteins in non-tumor chronic lung diseases.

PMID:39935527 | PMC:PMC11812559 | DOI:10.2147/JIR.S499029

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