JAMA. 2025 Apr 28. doi: 10.1001/jama.2025.2680. Online ahead of print.

ABSTRACT

IMPORTANCE: Non-cystic fibrosis (CF) bronchiectasis is a chronic lung condition caused by permanent bronchial dilatation and inflammation and is characterized by daily cough, sputum, and recurrent exacerbations. Approximately 500 000 people in the US have non-CF bronchiectasis.

OBSERVATIONS: Non-CF bronchiectasis may be associated with prior pneumonia, infection with nontuberculous mycobacteria or tuberculosis, genetic conditions (eg, α1-antitrypsin deficiency, primary ciliary dyskinesia), autoimmune diseases (eg, rheumatoid arthritis, inflammatory bowel disease), allergic bronchopulmonary aspergillosis, and immunodeficiency syndromes (eg, common variable immunodeficiency). Up to 38% of cases are idiopathic. According to US data, conditions associated with non-CF bronchiectasis include gastroesophageal reflux disease (47%), asthma (29%), and chronic obstructive pulmonary disease (20%). The prevalence of non-CF bronchiectasis increases substantially with age (7 per 100 000 in individuals 18-34 years vs 812 per 100 000 in those ≥75 years) and is more common in women than men (180 vs 95 per 100 000). Diagnosis is confirmed with noncontrast chest computed tomography showing dilated airways and often airway thickening and mucus plugging. Initial diagnostic evaluation involves blood testing (complete blood cell count with differential); immunoglobulin quantification testing (IgG, IgA, IgE, and IgM); sputum cultures for bacteria, mycobacteria, and fungi; and prebronchodilator and postbronchodilator spirometry. Treatment includes airway clearance techniques; nebulization of saline to loosen tenacious secretions; and regular exercise, participation in pulmonary rehabilitation, or both. Inhaled bronchodilators (β-agonists and antimuscarinic agents) and inhaled corticosteroids are indicated for patients with bronchiectasis who have asthma or chronic obstructive pulmonary disease. Exacerbations of bronchiectasis, which typically present with increased cough and sputum and worsened fatigue, are associated with progressive decline in lung function and decreased quality of life. Exacerbations should be treated with oral or intravenous antibiotics. Individuals with 3 or more exacerbations of bronchiectasis annually may benefit from long-term inhaled antibiotics (eg, colistin, gentamicin) or daily oral macrolides (eg, azithromycin). Lung transplant may be considered for patients with severely impaired pulmonary function, frequent exacerbations, or both. Among patients with non-CF bronchiectasis, mortality is higher for those with frequent and severe exacerbations, infection with Pseudomonas aeruginosa, and comorbidities, such as chronic obstructive pulmonary disease.

CONCLUSIONS AND RELEVANCE: Non-CF bronchiectasis is a chronic lung condition that typically causes chronic cough and daily sputum production. Exacerbations are associated with progressive decline in lung function and decreased quality of life. Management involves treatment of conditions associated with bronchiectasis, airway clearance techniques, oral or intravenous antibiotics for acute exacerbations, and consideration of long-term inhaled antibiotics or oral macrolides for patients with 3 or more exacerbations annually.

PMID:40293759 | DOI:10.1001/jama.2025.2680

J Inflamm Res. 2025 Apr 23;18:5499-5517. doi: 10.2147/JIR.S505229. eCollection 2025.

ABSTRACT

AIM: To identify the molecular signature of differentially expressed genes (DEGs) associated with PANoptosis in idiopathic pulmonary fibrosis (IPF) and to interpret their immune landscape and cellular distribution characteristics.

METHODS AND RESULTS: We acquired two IPF datasets from the Gene Expression Omnibus (GEO) database to identify PANoptosis-related DGEs (PAN-DEGs), initially identifying thirty PAN-DEGs. Utilizing machine learning algorithms, we established a five-gene PANoptosis-related signature comprising IGF1, GPX3, GADD45β, SMAD7, and TIMP3, each demonstrating robust diagnostic performance. The expression of these hub genes was subsequently validated using a third GEO dataset and a bleomycin-induced pulmonary fibrosis model. Immune infiltration analysis revealed a close association of these genes with various immune cells, and single-cell RNA sequencing indicated significant expression changes in diverse pulmonary cell types, particularly endothelial cells and fibroblasts.

CONCLUSION: We identified and validated a PANoptosis-related gene signature in IPF, providing insights into their immune infiltration and potential cellular distribution. Further research is necessary to elucidate the biological functions and mechanisms of these genes in the pathogenesis of IPF.

PMID:40291456 | PMC:PMC12034268 | DOI:10.2147/JIR.S505229

Toxicol Res. 2024 Dec 28;41(3):235-244. doi: 10.1007/s43188-024-00269-6. eCollection 2025 May.

ABSTRACT

Protein kinase B (PKB/AKT) is a very important member of the protein kinase family, playing significant roles in various crucial processes including insulin-signaling, cell survival, growth, and metabolism. The carboxyl-terminal modulator protein 1 (CTMP1) inhibits PKB, primarily by attenuating its phosphorylation. Idiopathic pulmonary fibrosis (IPF) is an irreversible, chronic, progressive pulmonary disorder; the clinical treatment options are limited. Of the various experimental models, bleomycin-induced lung fibrosis is the most extensively studied. It closely resembles human lung fibrosis. We explored the impact of CTMP1 on bleomycin-induced fibrosis. In vitro experiments involved knockdown of CTMP1 in A549 cells (human alveolar epithelial cells), followed by bleomycin treatment. In vivo, lung fibrosis was induced in mice with ablated CTMP1 via intratracheal bleomycin administration at 2 mg/kg. CTMP1 deletion reduced pulmonary fibrosis and the epithelial-to-mesenchymal transition by inhibiting PKB phosphorylation. These findings suggest that CTMP1 plays a pivotal role in the regulation of lung fibrosis, offering new insights into potential therapeutic approaches for IPF patients.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43188-024-00269-6.

PMID:40291111 | PMC:PMC12021751 | DOI:10.1007/s43188-024-00269-6

Front Med (Lausanne). 2025 Apr 11;12:1526530. doi: 10.3389/fmed.2025.1526530. eCollection 2025.

ABSTRACT

BACKGROUND: For patients with interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) with a progressive pulmonary fibrosis (PPF) phenotype, current knowledge of patient experience and symptom burden is limited. This study aimed to describe the patient journey for patients with PPF and IPF in a real-world setting in Japan.

METHODS: Data were analyzed from the Adelphi Real World PPF-ILD Disease Specific Programme™, a cross-sectional survey with elements of retrospective data collection of pulmonologists and rheumatologists in Japan from April to October 2022. Participants provided data for up to 12 consecutive patients with physician-confirmed ILD with a progressive phenotype. Analyses were descriptive, except Kappa (κ) statistic was used to measure the alignment between physician- and patient-reported symptom burden in the 4 weeks prior to survey date (poor agreement: κ =<0.00; slight 0.00-0.20; fair 0.21-0.40; moderate 0.41-0.60; substantial 0.61-0.80; almost perfect 1.00).

RESULTS: A total of 63 physicians (43 pulmonologists and 20 rheumatologists) provided data on 382 patients (312 with PPF and 70 with IPF). These patients were also asked to complete a voluntary survey on their experience and symptoms. Mean time from first symptom to consultation was 14.1 months for IPF, 8.0 months for non-connective tissue disease (CTD)-associated ILDs, and 10.7 months for CTD-ILDs. Mean times from consultation to diagnosis were 7.1, 4.8, and 3.6 months, respectively. Perception of symptoms differed between physicians and patients with alignment ranging from poor (dysphagia, κ = -0.0296, p = 0.6217) to substantial (weight loss, κ = 0.6174, p = 0.001). Health-related quality of life (HRQoL) was consistently impaired in patients overall, but too few patients completed HRQoL instruments to compare IPF with other forms of ILD.

CONCLUSIONS: This real-world study expands our understanding of the patient journey for patients with PPF and IPF in Japan. Greater communication between patients and physicians is needed to shorten diagnostic delays and target treatment strategies to improve patient experience and overall outcomes.

PMID:40291022 | PMC:PMC12023007 | DOI:10.3389/fmed.2025.1526530

Expert Rev Respir Med. 2025 Apr 27. doi: 10.1080/17476348.2025.2499651. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a rare progressive interstitial lung disease characterized by upper-lobe fibrosis, severe restrictive impairment, and poor prognosis. Unlike idiopathic pulmonary fibrosis, in which acute exacerbations, chronic respiratory failure, and lung cancer are the major causes of death, iPPFE primarily leads to progressive respiratory failure, often complicated by malnutrition and recurrent pneumothorax. Despite growing recognition, its pathogenesis remains unclear and no effective treatments exist.

AREAS COVERED: This review summarizes the epidemiological, clinical, radiological, and pathological features of iPPFE, as well as diagnostic and prognostic advancements. Key prognostic factors include weight loss, reduced forced vital capacity, hypercapnia, and lower-lobe interstitial pneumonia. Serum biomarkers (e.g. latent transforming growth factor-beta binding protein-4) are being explored for early detection and prognostic purposes. Although antifibrotic agents show limited efficacy, supportive care - pulmonary rehabilitation, nutritional management, and pneumothorax prevention - remains essential. Research on the fibroelastotic pathways may inform the development of future therapies.

EXPERT OPINION: IPPFE remains a challenging disease. Therefore, early diagnosis and comprehensive management of this condition are crucial. Future research should refine prognostic models and explore novel therapeutic approaches for treating fibroelastosis. Lung transplantation may be an option for select patients. Further studies are required to optimize these outcomes.

PMID:40289399 | DOI:10.1080/17476348.2025.2499651

Diagn Pathol. 2025 Apr 26;20(1):53. doi: 10.1186/s13000-025-01654-x.

ABSTRACT

OBJECTIVE: This case report describes a patient with acute fibrinous and organising pneumonia (AFOP) presenting with mass-like imaging on chest computed tomography (CT), aiming to enhance clinical awareness of this rare disease.

CASE PRESENTATION: A 66-year-old man presented with cough, sputum, chest tightness and weight loss persisting for 1 month. Chest X-ray revealed a space-occupying lesion in the left lung. Further CT imaging demonstrated irregular soft tissue masses in both the upper and lower lobes of the left lung. Although the imaging findings suggested lung cancer, the final pathological diagnosis confirmed AFOP. The patient was treated with methylprednisolone, resulting in substantial improvement of the upper lobe lesion, whereas the lower lobe lesion showed minimal response. Following the addition of mycophenolate mofetil, the lower lobe lesion decreased substantially. Multiple lung biopsies confirmed the diagnosis of AFOP, with no evidence of a malignant tumour.

CONCLUSIONS: Acute fibrinous and organising pneumonia presents with non-specific imaging findings, and when manifesting as a mass-like lesion, it may be misdiagnosed as lung cancer. Pathological examination remains essential for diagnosis. Close monitoring of the clinical response is crucial during treatment, and the treatment plan should be tailored to individual patient needs.

PMID:40287744 | DOI:10.1186/s13000-025-01654-x

Sci Rep. 2025 Apr 26;15(1):14622. doi: 10.1038/s41598-025-98490-2.

ABSTRACT

Emerging evidence suggests that N6-methyladenosine (m6A) modification significantly influences lung injury, lung cancer, and immune responses. The current study explores the potential involvement of m6A modification in the development of IPF. This research analyzed the GSE93606 dataset of 20 non-IPF and 154 IPF patients, identifying 26 m6A regulators and developing predictive models with RF and SVM, assessed via ROC curves. A nomogram was created with selected m6A factors, including molecular subtyping, PCA for m6A features, immune cell analysis, DEG identification, and functional enrichment. In vitro experiments on MRC-5 cells used RT-qPCR and Western blotting, and virtual drug screening targeted the WTAP protein through molecular docking. Analysis revealed 26 differential m6A regulators in IPF patients, with 16 significant; IGFBP2 and YTHDF2 were overexpressed, while others decreased. RF and SVM models identified predictive m6A regulators, and a nomogram was developed using five factors to predict IPF incidence. Distinct m6A patterns showed changes in RNA levels of specific genes in the BLM-induced group, and five compounds targeting WTAP were identified. This research explored m6A factors' impact on IPF diagnosis and prognosis, identifying WTAP as a potential biomarker.

PMID:40287490 | DOI:10.1038/s41598-025-98490-2

Molecules. 2025 Mar 21;30(7):1407. doi: 10.3390/molecules30071407.

ABSTRACT

Fennel waste is rich in compounds that may have beneficial effects on human health. For this reason, the most abundant metabolites in fennel were isolated as the following: quercetin-3-O-glucoside, quinic acid, 1,5-dicaffeoylquinic acid, kaempferol-3-O-glucuronide, and quercetin-3-O-glucuronide. After inducing inflammation in human bronchial epithelial cells by stimulating them with IL-1β, the cells were treated with the specialized Foeniculum vulgare metabolites at different concentrations to assess their anti-inflammatory effect. Eicosanoids, fatty acids, and sphingolipids were extracted from the cell medium and quantified by UPLC-ESI-QTRAP-MS/MS analysis. The anti-inflammatory activity of the metabolites isolated from fennel waste was demonstrated. They were able to alleviate the inflammatory state in human bronchial epithelium by modulating the metabolic expression of both pro- and anti-inflammatory eicosanoids, fatty acids, and sphingolipids. These findings suggest the potential use of fennel waste in the production of dietary supplements to alleviate the symptoms of chronic inflammatory diseases like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), where the continuous use of antiphlogistics may have significant side effects.

PMID:40286023 | DOI:10.3390/molecules30071407

Life (Basel). 2025 Mar 21;15(4):516. doi: 10.3390/life15040516.

ABSTRACT

There is increasing evidence supporting the use of morphofunctional assessment (MFA) as a tool for clinical characterization and decision-making in malnourished patients. MFA enables the diagnosis of malnutrition, sarcopenia, obesity, and cachexia, leading to a novel phenotype-based classification of nutritional disorders. Bioelectrical impedance analysis (BIVA), nutritional ultrasound® (NU) and computed tomography (CT) are included, along with functional tests like the Timed Up and Go test (TUG). Myoesteatosis, detectable via CT, can occur independently from nutritional phenotypes and has been identified as a significant mortality predictor in idiophatic pulmonary fibrosis (IPF). Our aim is to analyze the prevalence and overlap of nutritional phenotypes in IPF and evaluate the prognostic value of myoesteatosis. Our bicenter cross-sectional study included 82 IPF patients (84.1% male and with a medium age of 71.1 ± 7.35 years). MFA was performed using BIVA, NU, CT at the T12 level (CT-T12), the handgrip strength (HGS) test, and the TUG. CT-T12 BC parameters were analyzed using FocusedON® software, while statistical analyses were conducted with JAMOVI version 2.3.22. All four major nutritional phenotypes were represented in our cohort, with significant overlap. A total of 80.5% met the GLIM criteria for malnutrition, 14.6% had cachexia, 17% were sarcopenic, and 28% were obese. Of the obese patients, 70% were also malnourished, while 100% of sarcopenic obese patients (5.9% of total) had malnutrition. A total of 55% of sarcopenic patients with available CT also had myosteatosis, suggesting muscle quality deterioration as a potential driver of functional impairment. The presence of myosteatosis > 15% in T12-CT was an independent predictor of 12-month mortality (HR = 3.13; 95% CI: 1.01-9.70; p = 0.049), with survival rates of 78.1% vs. 96.6% in patients with vs. without myosteatosis, respectively. To conclude, this study underscores the relevance of MFA in the nutritional characterization of patients with IPF, demonstrating its potential to identify specific phenotypes associated with malnutrition, functional impairment, and the presence of myoesteatosis, thereby providing a valuable tool for clinical decision-making.

PMID:40283071 | DOI:10.3390/life15040516

Medicina (Kaunas). 2025 Mar 26;61(4):599. doi: 10.3390/medicina61040599.

ABSTRACT

Usual Interstitial Pneumonia (UIP) is the most severe radiological/histological pattern of Interstitial Lung Disease (ILD). It is typical of Idiopathic Pulmonary Fibrosis (IPF), but is also frequently described in Autoimmune Rheumatic Diseases (ARDs), sharing with IPF common risk factors, genetic backgrounds, and in some cases, disease progression and prognosis. Following the results of the PANTHER study, immunosuppressive drugs are now not recommended for the treatment of IPF; however, their use for the treatment of UIP secondary to ARDs is still under debate. The aim of this review is to summarize existing knowledge on the clinical presentation of autoimmune UIP and its treatment with immunosuppressive drugs. We searched PubMed for English language clinical trials and studies on treatment of ARDs-ILD, looking for specific treatments of UIP-ARDs. The available clinical trials rarely stratify patients by ILD pattern, and clinical studies generally lack a comparison with a placebo group. In Systemic Sclerosis, UIP patients showed a non-significant trend of worsening under immunosuppression. On the contrary, in Interstitial Pneumonia with Autoimmune Features and, above all, Rheumatoid Arthritis, immunosuppressive treatment produced promising results in the management of UIP patients. In conclusion, the current evidence about the immunosuppressive treatment of UIP-ARDs is limited and conflicting. There is an urgent need to adequately assess this topic with specific clinical trials, as has already been performed for IPF. The possibility should be considered that different ARDs can respond differently to immunosuppression. Finally, a wider use of histological samples could produce valuable information from a diagnostic, therapeutic, and research point of view.

PMID:40282891 | DOI:10.3390/medicina61040599

AAPS PharmSciTech. 2025 Apr 25;26(5):113. doi: 10.1208/s12249-025-03112-9.

ABSTRACT

In this study, a quercetin-loaded liposome system modified with collagenase was developed to increase QU penetration in the ECM and improve IPF treatment. Quercetin-loaded long circulation liposome (QU-LP) and quercetin-loaded liposome modified with collagenase type I (QU-CLP) were prepared, followed by characterization of the encapsulation efficiency, particle size, morphology, and in vitro drug release. Their effect on the cytotoxicity of A549 cells was detected by the Cell Counting Kit-8, and the cellular uptake was investigated using cellular fluorescence imaging and flow cytometry. TGF-β1 induced A549 cell model was established to mimic pulmonary fibrosis to explore further the anti-pulmonary fibrosis effect of QU-CLP by CCK8 experiment. QU-CLP significantly improves the solubility and bioavailability of QU by encapsulating it in the internal cavity with a high encapsulation efficiency (EE%) of 92.86 ± 1.03%. Liposomes alleviate the influence of QU on normal A549 cell growth. Enhanced fluorescence intensity was observed in A549 cells treated with coumarin 6-labeled and collagenase-modified nanoliposomes (C6-CLP) after 4 h of incubation on the collagen matrix, confirming that collagenase-loaded liposomes could penetrate the collagen barrier and cells internalized more hydrophobic drug. The mean fluorescence intensity (MFI) of the C6-CLP group was 2.88 times that of the C6-labeled nanoliposomes (C6-LP). Moreover, QU-CLP significantly (**P < 0.01) inhibited the proliferation of A549 cells stimulated by TGF-β1. QU-CLP has excellent potential for delivering QU with enhanced bioavailability, high cellular uptake efficiency, and improved therapeutic efficacy in IPF.

PMID:40281247 | DOI:10.1208/s12249-025-03112-9

Lung. 2025 Apr 25;203(1):57. doi: 10.1007/s00408-025-00811-9.

ABSTRACT

PURPOSE: Combined lung-liver transplant (CLLT) is a complex yet life-saving procedure for patients with simultaneous end-stage lung and liver disease. Given the geographical allocation change to the lung allocation score (LAS) in 2017 and the recent SARS-CoV-2 outbreak in 2019, we aim to provide an updated analysis of the patient selection and outcomes of CLLTs.

METHODS: The UNOS registry was used to identify all patients who underwent CLLT between January 2014 and June 2023. To account for the changes made to LAS in 2017, baseline characteristics and outcomes were compared between era 1 (before 2017) and era 2 (after 2017). Risk factors for mortality were analyzed using the Cox regression hazard models. Recipient survival of up to 3 years was analyzed using the Kaplan-Meier method.

RESULTS: 117 CLLTs were performed (77.8% in era 2). Donor organs experienced significantly longer ischemic times (p = 0.039) and traveled longer distances (p = 0.025) in era 2. However, recipient (p = 0.79) and graft (p = 0.41) survival remained comparable at up to 3 years post-transplant between eras. CLLTs demonstrated similar long-term survival to isolated lung transplants (p = 0.73). Higher recipient LAS was associated with an increased mortality risk (HR 1.14, p = 0.034). Recipient diagnosis of idiopathic pulmonary fibrosis carried a 5.03-fold risk of mortality (p = 0.048) compared to those with cystic fibrosis.

CONCLUSION: In the post-2017 LAS change era, CLLTs are increasingly performed with comparable outcomes to isolated lung transplants. A careful, multidisciplinary approach to patient selection and management remains paramount to optimizing outcomes for this rare patient population.

PMID:40281222 | DOI:10.1007/s00408-025-00811-9

Sci Rep. 2025 Apr 25;15(1):14448. doi: 10.1038/s41598-025-97037-9.

ABSTRACT

To investigate the molecular mechanisms underlying idiopathic pulmonary fibrosis (IPF), we analyzed the GSE173355 and GSE173356 datasets obtained from the NCBI-GEO database. We identified differentially expressed genes (DEGs) and differentially methylated sites. Functional enrichment analysis was conducted for both DEGs and differentially methylated sites. Functional enrichment analysis was performed for both DEGs and differentially methylated sites, alongside an examination of immune-related scores, proportions, and GSVA enrichment scores of immune cells in IPF versus control samples. An integrated gene-methylation association analysis revealed 8 genes with expression levels negatively influenced by methylation. The Rap1 pathway, Focal adhesion, and Axon guidance were significantly enriched among both DEGs and differentially methylated sites. Immune-related scores were notably lower in the IPF group compared to the control group, with marked differences in immune cell proportions and GSVA enrichment scores. Screening of DEGs identified 361 differentially expressed immune-related genes (IRGs). Protein-protein interaction (PPI) network analysis using the STRING database and Cytoscape software unveiled 10 key genes and 3 core subnetworks. RT-qPCR validation in bleomycin-induced IPF mouse model and A549 EMT model confirmed the reliability of most findings. These results provide new insights into IPF pathogenesis and potential therapeutic strategies, necessitating further functional validation.

PMID:40280949 | DOI:10.1038/s41598-025-97037-9

Free Radic Biol Med. 2025 Apr 23:S0891-5849(25)00244-8. doi: 10.1016/j.freeradbiomed.2025.04.034. Online ahead of print.

ABSTRACT

Mitochondrial oxidative damage-mediated dysfunction is implicated in pulmonary pathogenesis, yet the molecular mechanisms linking redox imbalance to pulmonary fibrosis remain elusive. In this study, we demonstrate that DNA methyltransferase 3A (DNMT3A) drives fibroblast activation and pulmonary fibrosis by epigenetically repressing superoxide dismutase 2 (SOD2), a critical antioxidant enzyme. Using fibroblast-specific DNMT3A-deficient mice and bleomycin-induced pulmonary fibrosis models, we observed that DNMT3A ablation significantly attenuated mitochondrial oxidant overproduction, restored mitochondrial membrane potential (MMP), and reduced fibrotic progression. Mechanistically, DNMT3A directly bound to the SOD2 promoter, inducing hypermethylation and transcriptional silencing, which exacerbated oxidative stress and fibroblast proliferation. Conversely, AAV6-mediated SOD2 overexpression or DNMT3A knockdown rescued SOD2 expression, suppressed mitochondrial oxidative burden, and ameliorated fibrosis. Clinically, idiopathic pulmonary fibrosis (IPF) patient tissues exhibited elevated DNMT3A levels, diminished SOD2 expression, and marked mitochondrial dysfunction, corroborating our experimental findings. These results unveil a novel DNMT3A/SOD2 axis as an epigenetic regulator of mitochondrial redox dysregulation-driven fibrosis, providing a potential therapeutic avenue for targeting oxidative damage in pulmonary fibrotic disorders.

PMID:40280315 | DOI:10.1016/j.freeradbiomed.2025.04.034

Biochem Pharmacol. 2025 Apr 23:116959. doi: 10.1016/j.bcp.2025.116959. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a disease that includes inflammation and scarring of the lung tissues. Cyclin-dependent kinase 8 (CDK8) is a target of interest due to its role in inflammatory pathways. CDK8 can also modulate the TGF-β/Smad signaling associated with IPF. Herein, a structure-based virtual screening (SBVS) campaign led to the identification of three CDK8 inhibitors. Testing of candidate inhibitors in protein and cellular assays confirmed CDK8 inhibition, with the most potent inhibitor producing an IC50 value of 398.8 nM. Computational analysis identified pharmacological interactions that lead to CDK8 inhibition. No significant cytotoxicity was observed when the inhibitor was treated in vitro. Further results showed that the inhibitor can disrupt proteins associated with the epithelial-mesenchymal transition (EMT) and reduce cell migration. Additionally, the inhibitor can disrupt the TGF- β1/Smad signaling axis in the nucleus, potentially impacting the transcription of IPF related protein expression, when treated in cells at 5 µM. Comparisons to structures of known CDK8 inhibitors showed the identified inhibitor to be structurally novel. When tested against a panel of kinases at 1 µM, the most potent inhibitor demonstrated a favorable CDK8 selectivity profile. The identification of the CDK8 inhibitors in this study can be used in future drug design studies and as CDK8 probes to explore alternative therapeutics for IPF.

PMID:40280247 | DOI:10.1016/j.bcp.2025.116959

Cell Biol Toxicol. 2025 Apr 25;41(1):73. doi: 10.1007/s10565-025-10031-9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast activation and collagen deposition, is a progressive lung disease that lacks effective interventions. Ubiquitin-specific peptidase 10 (USP10) acts as a multifunctional player in inflammatory response and progression of cancers, the effect on pulmonary fibrosis is unknown. Here, we demonstrated downregulated expression of USP10 in fibrotic lung tissues of IPF patients. In the current study, lung tissues were collected at the end of weeks 1, 2, or 3 post bleomycin (BLM)-intratracheal delivery. Consistently, USP10 expression levels were reduced after BLM challenge in a time-dependent manner. Mice treated with lentivirus overexpressing USP10 exhibited mitigative lung injury and reduced collagen deposition. USP10 overexpression enhanced autophagy in BLM-treated mouse lungs. Interestingly, the protective effect of USP10 was attenuated as the pulmonary autophagy flux was blocked by autophagy inhibitor 3-methyladenine (3-MA). Primary human and mouse lung fibroblasts were treated with pro-fibrotic TGF-β1 to verify the role of USP10 in vitro. Mechanically, the deubiquitinating enzyme USP10 interacted with Sirtuin 6 (Sirt6) and inhibited its degradation. Furthermore, USP10 overexpression inhibited the activation of Sirt6-mediated AKT/mTOR pathway in both lung tissues and fibroblasts. Our findings suggest that USP10 might attenuate pulmonary fibrosis through the promotion of Sirt6/AKT/mTOR-mediated autophagy. These data prioritize USP10 as a therapeutic target for treating IPF.

PMID:40278953 | DOI:10.1007/s10565-025-10031-9

Infect Dis Rep. 2025 Apr 3;17(2):28. doi: 10.3390/idr17020028.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of conditions that can cause fibrosis of the lung interstitium, resulting in respiratory failure and death. Patients with an ILD, particularly idiopathic pulmonary fibrosis (IPF) or connective tissue disease-associated ILDs (CTD-ILDs), are prone to develop chronic pulmonary infections such as tuberculosis (TB) and non-tuberculous mycobacterial pulmonary disease (NTM-PD).

METHODS: This case series examines the management of three ILD patients with a usual interstitial pneumonia (UIP) pattern and concomitant NTM-PD or TB at National Institute for Infectious Diseases "Lazzaro Spallanzani" in Rome, Italy, over three years (2019-2022).

RESULTS AND CONCLUSIONS: Multi-disciplinary discussion (MDD) was crucial to define the therapeutic approach due to the increased risk of side effects and drug interactions. Our work underscored how a comprehensive diagnostic evaluation, enriched by MDD, is useful for optimizing the management and reducing drug-related adverse effects and interactions in ILD patients with cavitary lesions.

PMID:40277955 | DOI:10.3390/idr17020028

Adv Respir Med. 2025 Mar 28;93(2):6. doi: 10.3390/arm93020006.

ABSTRACT

Background: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is one of the most challenging events in the disease course due to the high mortality despite treatment. The role of corticosteroid treatment in AE-IPF has never been defined, even though it is used in current clinical practice. We performed a meta-analysis to determine the effects of steroid treatment on the acute exacerbation outcomes in idiopathic pulmonary fibrosis (IPF). Objectives: To evaluate the impact of steroids on mortality in patients affected by an acute exacerbation of IPF. Methods: This meta-analysis was performed in accordance with the PRISMA statement. A systemic literature search was conducted through Google Scholar, Scopus, WoS, PubMed, and JSTOR. Manuscripts from January 2014 to September 2024 were included in the analysis. Articles were included on whether participants had an acute exacerbation of IPF. Regarding the intervention performed, we evaluated the studies in which patients underwent treatment with corticosteroids. As outcomes, studies were included if they analyzed the overall mortality. Results: A total of 2156 records were initially identified. Nineteen studies (3277 patients) were ultimately included in the final analysis, comparing 1552 patients who received steroids to 1725 patients without steroids. Steroid treatment poses a higher risk, as suggested by the summary measures (RR of 1.78; CI 1.29-2.76, p = 0.00001). Conclusions: This meta-analysis investigated the debated role of corticosteroid treatment during acute exacerbation of idiopathic pulmonary fibrosis. Overall, steroid therapy is associated with increased risk. Clinicians should carefully weigh the risks and benefits of corticosteroid therapy in acute exacerbation of IPF.

PMID:40277510 | DOI:10.3390/arm93020006

J Comput Aided Mol Des. 2025 Apr 25;39(1):19. doi: 10.1007/s10822-025-00596-2.

ABSTRACT

Ubiquitin-specific proteases (USPs) are crucial regulators of protein degradation pathways, influencing diverse cellular processes and disease mechanisms. Among them, USP30 plays a pivotal role in mitochondrial quality control and has been implicated in idiopathic pulmonary fibrosis (IPF), a chronic lung disease for which current therapies merely slow disease progression. The high flexibility of USP30's catalytic site, coupled with its dependence on covalent interaction with the catalytic cysteine presents significant challenges in discovering suitable small molecule inhibitors. In this study, we identified three non-covalent small molecule inhibitors for USP30 using molecular modeling, X-ray crystallography, and virtual screening. These findings offer valuable insights and novel chemical starting points for further medicinal chemistry optimization.

PMID:40274689 | DOI:10.1007/s10822-025-00596-2

J Ethnopharmacol. 2025 Apr 22:119866. doi: 10.1016/j.jep.2025.119866. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Saengmaek-san (SMS) is a herbal prescription comprising Liriope platyphylla, Panax ginseng, and Schisandra chinensis. In traditional Korean medicine (TKM), SMS has been used to treat a condition known as the dual deficiency of qi and yin in the lungs, a syndrome characterized by the depletion of vitality and body fluids, often resulting from heat exhaustion. SMS has primarily been used to promote fluid production, alleviate dry cough, and relieve progressive dyspnea.

AIM OF THE STUDY: The current study was planned to explore the efficacy and underlying mechanisms of SMS in managing idiopathic pulmonary fibrosis.

MATERIALS AND METHODS: In mice with bleomycin-induced pulmonary fibrosis, the SMS water extract was administered at doses of 50, 150, and 450 mg/kg twice daily for 14 days. The extent of pulmonary fibrosis was assessed using the Ashcroft scale in stained lung tissues. The levels of transforming growth factor-β, α-smooth muscle actin (α-SMA), and collagen accumulation were also evaluated. Bronchoalveolar lavage fluid (BALF) was collected to measure the total cell counts, white blood cell ratios, and cytokine levels (IL-6 and IL-10).

RESULTS: We observed statistically significant and potential anti-fibrotic effects in the SMS 450 mg/kg treatment group in terms of preventing body weight loss, decreasing Ashcroft scale, and reducing macrophage and granulocyte counts in BALF, as well as reducing α-SMA and collagen production. Additionally, an increase was observed in the levels of anti-inflammatory cytokine IL-10.

CONCLUSIONS: SMS demonstrated potential as a therapeutic candidate for idiopathic pulmonary fibrosis by exerting anti-inflammatory effects and reducing collagen deposition.

PMID:40274032 | DOI:10.1016/j.jep.2025.119866