Cureus. 2025 Jul 8;17(7):e87536. doi: 10.7759/cureus.87536. eCollection 2025 Jul.

ABSTRACT

We present the case of a 72-year-old man with idiopathic pulmonary fibrosis (IPF) who presented with stiffness and pelvic girdle pain and was initially treated for polymyalgia rheumatica (PMR). Despite transient improvement on steroids, persistent symptoms and atypical MRI findings led to muscle and renal biopsies, revealing necrotizing vasculitis and pauci-immune glomerulonephritis. Positive myeloperoxidase and perinuclear antineutrophil cytoplasmic antibody titers confirmed the diagnosis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The patient's course was complicated by diffuse alveolar hemorrhage requiring intubation, which improved with pulse steroids and cyclophosphamide. The patient stabilized on methotrexate and methylprednisolone. This case highlights the complexity of diagnosing AAV, especially with overlapping PMR-like symptoms and underlying interstitial lung disease.

PMID:40777707 | PMC:PMC12331196 | DOI:10.7759/cureus.87536

bioRxiv [Preprint]. 2025 Jul 24:2025.07.23.666333. doi: 10.1101/2025.07.23.666333.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease marked by aberrant fibroblast-to-myofibroblast differentiation, a process that requires metabolic reprogramming. We identify alanine as a critical metabolite that confers metabolic flexibility to support differentiation. TGF-β increases alanine by activating both its synthesis and import in normal and IPF lung fibroblasts. Alanine is synthesized primarily by GPT2, which is regulated by a glutamine-glutamate-α-ketoglutarate axis. Inhibiting GPT2 depletes alanine and suppresses TGF-β-induced expression of α-SMA and COL1A1, an effect reversed by alanine supplementation. We also identify SLC38A2 as a key transporter of both alanine and glutamine that is upregulated by TGF-β and alanine deprivation. Together, SLC38A2 and GPT2 activities converge to maintain intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency suppresses glycolysis and depletes tricarboxylic acid cycle intermediates, while supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly in the absence of glutamine. Combined inhibition of GPT2 and SLC38A2 suppresses fibrogenic responses in fibroblasts and in human precision-cut lung slices, highlighting a potential therapeutic strategy for fibrotic lung disease.

PMID:40777505 | PMC:PMC12330655 | DOI:10.1101/2025.07.23.666333

bioRxiv [Preprint]. 2025 Jul 22:2025.07.22.665497. doi: 10.1101/2025.07.22.665497.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is a fatal lung disease of progressive lung parenchymal scarring caused by the aberrant response of an alveolar epithelium repeatedly exposed to injury. Understanding epithelial dysfunction has been hampered by the lack of physiological alveolar type 2 (AT2) cell models and defined disease triggers. Monogenic forms of familial pulmonary fibrosis (FPF) caused by toxic gain-of-function variants provide an opportunity to investigate early pathogenic events. One such variant, surfactant protein C (SFTPC)-I73T, abnormally localises within AT2 cells and causes their dysfunction.

METHODS: We used base editing of fetal lung-derived AT2 (fdAT2) organoids to create a heterozygous disease model of endogenous SFTPC-I73T expression. We also created an inducible overexpression system to interrogate temporal changes associated with SFTPC-I73T expression. We cultured fdAT2 both in 3D culture and at air-liquid interface to understand the importance of polarity cues and air exposure on disease phenotypes.

RESULTS: In our heterozygous endogenous expression system, we found that fdAT2 expressing SFTPC-I73T grew without a lumen and were unable to correctly polarise. SFTPC-I73T accumulated with time and caused gross enlargement of early endosomes, preventing correct apico-basal trafficking of multiple endosomally trafficked cargoes including polarity markers and cell adhesion proteins. This phenotype was exacerbated by air exposure and led to loss of epithelial monolayer integrity and abnormal wound healing after injury.

CONCLUSION: Using endogenous gene editing for the first time in differentiated alveolar organoids, we have demonstrated that the pathogenic effects of SFTPC-I73T are mediated through endosomal dysfunction and abnormal epithelial organisation. This has important implications for AT2 function in vivo .

PMID:40777458 | PMC:PMC12330739 | DOI:10.1101/2025.07.22.665497

bioRxiv [Preprint]. 2025 Jul 26:2025.07.24.665373. doi: 10.1101/2025.07.24.665373.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which novel therapeutic approaches are desperately needed. Inhibitor of DNA binding (ID) proteins are regulated by Transforming Growth Factor-β. However, the regulation and the effects of ID proteins in IPF remain poorly understood. We aimed to assess the expression of ID proteins in IPF and determine the effects of ID proteins on human lung fibroblasts (HLF) in vitro and pulmonary fibrosis in vivo .

METHODS: The expression of ID proteins in lungs and lung fibroblasts from mice and human patients with pulmonary fibrosis was evaluated. The effects of ID1/ID3 inhibition and overexpression on HLF were assessed. Genetic and pharmacological approaches were used in vivo to determine the role of ID1/ID3 in pulmonary fibrosis.

RESULTS: ID1/ID3 levels were elevated in HLFs isolated from pulmonary fibrosis-diseased patients and mice. ID1/ID3 knockdown decreased IPF-diseased HLF proliferation and differentiation into myofibroblasts. Bleomycin-exposed ID1/ID3 KO mice displayed improved lung function and presented with decreased lung fibrosis when compared to WT mice. A pharmacological inhibitor of ID1/ID3 decreased IPF-diseased HLF proliferation and differentiation in vitro and attenuated pulmonary fibrosis in vivo . A lung specific inhibition of ID1/ID3, using adeno-associated viruses expressing short hairpins targeting ID1 and ID3, reversed pulmonary fibrosis in mice. Mechanistically, ID1/ID3 inhibition decreased fibroblast proliferation through cell cycle genes and inhibited fibroblast differentiation through the MEK/ERK pathway.

CONCLUSIONS: Our data indicate that a simultaneous inhibition of ID1 and ID3 attenuates pulmonary fibrosis. ID1/ID3 inhibition holds potential as a novel therapeutic treatment for IPF.

PMID:40777426 | PMC:PMC12330687 | DOI:10.1101/2025.07.24.665373

BMC Pulm Med. 2025 Aug 7;25(1):378. doi: 10.1186/s12890-025-03836-1.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and serious lung disease with a poor prognosis and severe clinical and humanistic burden. This systematic literature review and meta-analysis aimed to summarize and quantify the data on IPF incidence and prevalence among adults within the general population and to compare regional differences.

METHODS: Comprehensive searches of MEDLINE®, Embase, and the Cochrane Database of Systematic Reviews were conducted to capture available studies published in English from January 1, 2000, to November 7, 2023, that reported on the incidence or prevalence of IPF. Pooled weighted-mean incidence and prevalence estimates were calculated from studies reporting adequate epidemiological data using a DerSimonian-and-Laird random-effects model.

RESULTS: Of 4,077 records identified, 26 studies were included in the meta-analysis (17 reported both prevalence and incidence, 6 reported incidence only, 3 reported prevalence only). Most studies were retrospective, with study periods ranging from 1984 to 2021. Pooled global incidence per 100,000 (95% confidence interval) was 5.8 (4.8, 6.8; 23 studies). Pooled incidence in Asia was 4.4 (1.6, 7.2; 5 studies), 5.1 (3.9, 6.3; 13 studies) in Europe, and 9.0 (6.9, 11.1; 5 studies) in North America. Pooled prevalence (per 100,000) was 17.7 (14.0, 21.5; 20 studies) globally, 14.8 (7.1, 22.6; 6 studies) in Asia, 14.6 (9.4, 19.7; 9 studies) in Europe, and 27.2 (21.0, 33.4; 6 studies) in North America.

CONCLUSION: This analysis confirms that IPF is a rare condition globally, but substantial heterogeneity exists across studies. Incidence and prevalence were notably high in North America compared with Europe and Asia. This finding may be explained by the use of selective source populations in North American studies, in contrast to the more general populations used in European or Asian studies. Additional contributing factors include variations in case identification algorithms, differences in diagnostic definitions and regional differences in occupational and environmental exposures. While recent multi-societal guidelines have advanced the standardization of the IPF diagnostic process, variability in clinical practice remains a challenge that affects comparisons of incidence and prevalence across regions and over time.

PMID:40775309 | DOI:10.1186/s12890-025-03836-1

Gene. 2025 Aug 5:149717. doi: 10.1016/j.gene.2025.149717. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), the most common interstitial lung disease, has a severe prognosis, and its diagnosis is difficult. Long non-coding RNAs (lncRNAs) play crucial roles in the mechanism of IPF and exhibit great potential as biomarkers. Past research found that HOXD antisense growth-associated lncRNA (HAGLR) was elevated in IPF. Therefore, this study assessed the diagnostic utility and function of HAGLR in IPF.

METHOD: HAGLR expression was screened in the Gene Expression Omnibus datasets. Then, the serum specimens and clinical information of 66 patients with IPF, 93 patients with interstitial lung disease (ILD) without IPF, 61 patients with pneumonia, and 58 healthy controls were simultaneously collected. HAGLR expression was tested in all subjects and analyzed using receiver operating characteristic curves to verify the clinical utility of HAGLR. Then, the effects of HAGLR inhibition on fibrosis-related gene and protein expression in a cell model of fibrosis were investigated by quantitative reverse transcription-polymerase chain reaction and western blotting.

RESULTS: HAGLR expression was higher in patients with IPF than in healthy controls, patients with ILD without IPF, and patients with pneumonia. The ROC curve analysis illustrated that HAGLR can distinguish patients with IPF from healthy controls. A model combining clinical items (including age, gender, routine blood test, tumor biomarkers, and cytokines), with HAGLR displayed good clinical value, with an are under the curve of 0.994, sensitivity of 100.0% and specificity of 91.4%. Upon HAGLR inhibition, fibrosis proteins were downregulated.

CONCLUSION: HAGLR has utility in the auxiliary diagnosis of IPF, as it can differentiate IPF from other conditions. HAGLR inhibition could alleviate fibrosis at the cellular level.

PMID:40774525 | DOI:10.1016/j.gene.2025.149717

Semin Respir Crit Care Med. 2025 Aug 7. doi: 10.1055/a-2657-9494. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer deaths worldwide, claiming more lives than other age-related and screen-detectable cancers. Cigarette smoking remains the most important risk factor. However, despite common perceptions, risk is not related solely to cigarette smoking. Several vulnerable and special populations experience a disproportionate burden of lung cancer, often complicated by overlapping medical issues, diagnostic challenges, and treatment limitations. This review highlights four populations (people with HIV, persons who are immunocompromised, lung cancer in nonsmoking women, and individuals with interstitial lung disease [ILD]) who experience unique risks that impact early detection, diagnosis, and management of lung cancer. Three of these populations are frequently underrepresented in clinical trials, yet they may be at elevated risk due to chronic inflammation, immune dysregulation, or previous medical therapies. Individuals with HIV have a significantly increased incidence of lung cancer, often presenting at younger ages and with more advanced disease. Similarly, patients who are immunocompromised following organ or stem cell transplantation are at heightened risk due to prolonged immune dysfunction and prior exposures to toxic therapies. Individuals with ILD, especially idiopathic pulmonary fibrosis (IPF), have an increased risk of developing lung cancer, which is challenging to detect with imaging given architectural distortion and even more challenging to treat given limited pulmonary reserve. We also highlight women, as there has been a striking trend of rising incidence of lung cancer among women worldwide, particularly among those who have never smoked. The intersection of these risks with traditional lung cancer risk factors like tobacco smoking highlights a critical need for increased awareness, improved risk stratification, and adapted screening strategies that take these complexities into account. In this review, we explore the epidemiology, clinical presentation, and early detection and management challenges unique to each population, underscoring the necessity of precision approaches to support individualized care.

PMID:40774326 | DOI:10.1055/a-2657-9494

Respir Investig. 2025 Aug 6;63(5):1012-1017. doi: 10.1016/j.resinv.2025.07.021. Online ahead of print.

ABSTRACT

BACKGROUND: Interstitial lung disease (ILD) prognostication incorporates clinical history, pulmonary function testing (PFTs), and chest CT pattern classifications. The machine learning classifier, Fibresolve, includes a model to help detect CT patterns associated with idiopathic pulmonary fibrosis (IPF). We developed and tested new Fibresolve software to predict outcomes in patients with ILD.

METHODS: Fibresolve uses a transformer (ViT) algorithm to analyze CT imaging that additionally embeds PFTs, age, and sex to produce an overall risk score. The model was trained to optimize risk score in a dataset of 602 subjects designed to maximize predictive performance via Cox proportional hazards. Validation was completed with the first hazard ratio assessment dataset, then tested in a second datatest set.

RESULTS: 61 % of 220 subjects died in the validation set's study period, whereas 40 % of the 407 subjects died in the second dataset's. The validation dataset's mortality hazard ratio (HR) was 3.66 (95 % CI: 2.09-6.42) and 4.66 (CI: 2.47-8.77) for the moderate and high-risk groups. In the second dataset, Fibresolve was a predictor of mortality at initial visit, with a HR of 2.79 (1.73-4.49) and 5.82 (3.53-9.60) in the moderate and high-risk groups. Similar predictive performance was seen at follow-up visits, as well as with changes in the Fibresolve scores over sequential visits.

CONCLUSION: Fibresolve predicts mortality by automatically assessing combined CT, PFTs, age, and sex into a ViT model. The new software algorithm affords accurate prognostication and demonstrates the ability to detect clinical changes over time.

PMID:40774166 | DOI:10.1016/j.resinv.2025.07.021

Cureus. 2025 Jul 7;17(7):e87461. doi: 10.7759/cureus.87461. eCollection 2025 Jul.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) characterized by progressive fibrosis and poor survival outcomes. Accurate diagnosis and prognosis remain challenging due to overlapping features with other ILDs and variability in imaging interpretation. This systematic review evaluates the current evidence on artificial intelligence (AI) and machine learning (ML) applications for the diagnosis and prognosis of IPF using computed tomography (CT) imaging. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, eight studies published between 2017 and 2024 were included, demonstrating promising results across various methodologies, including deep learning (DL) models, support vector machines (SVMs), and ensemble approaches. AI-derived parameters, particularly measures of fibrotic burden and pulmonary vascular volume, consistently outperformed conventional visual CT scores for prognostication. Strong correlations between AI-quantified CT features and pulmonary function (PF) tests suggest potential surrogate markers for physiological parameters. Novel prognostic biomarkers identified through AI analysis expand understanding beyond traditional parenchymal assessment. Despite these advances, limitations include retrospective designs, sample size constraints, male-predominant cohorts, and limited external validation. Future research should prioritize large, prospective, multi-center studies with diverse populations, standardized protocols, explainable AI (XAI) techniques, and integration into clinical workflows to realize the transformative potential of AI for improving IPF management.

PMID:40772136 | PMC:PMC12327841 | DOI:10.7759/cureus.87461

Geroscience. 2025 Aug 6. doi: 10.1007/s11357-025-01819-y. Online ahead of print.

ABSTRACT

Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.

PMID:40770529 | DOI:10.1007/s11357-025-01819-y

Nat Commun. 2025 Aug 6;16(1):7234. doi: 10.1038/s41467-025-62431-4.

ABSTRACT

Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin (BLM) -induced fibrotic lungs of young and aged male mice, at 3 time points corresponding to the peak of fibrosis, regeneration, and resolution. We find that lung injury shifts the transcriptomic profiles of three pulmonary capillary endothelial cells (PCEC) subpopulations. The associated signatures are linked to pro-angiogenic signaling with strong Lrg1 expression and do not progress similarly throughout the resolution process between young and old animals. Moreover, part of this set of resolution-associated markers is also detected in PCEC from samples of patients with idiopathic pulmonary fibrosis. Finally, we find that aging also alters the transcriptome of PCEC, which displays typical pro-fibrotic and pro-inflammatory features. We propose that age-associated alterations in specific PCEC subpopulations may interfere with the process of lung progenitor differentiation, thus contributing to the persistent fibrotic process typical of human pathology.

PMID:40769983 | DOI:10.1038/s41467-025-62431-4

Eur Respir Rev. 2025 Aug 6;34(177):250023. doi: 10.1183/16000617.0023-2025. Print 2025 Jun.

ABSTRACT

Several interstitial lung diseases (ILDs) with different aetiologies and pathogenic mechanisms may exhibit a progressive behaviour, similar to idiopathic pulmonary fibrosis, with comparable functional decline and early mortality. Progressive pulmonary fibrosis (PPF) is not a diagnosis but rather reflects a clinical phenotype. Identifying progression is challenging as variability exists, both between different ILDs as well as in the context of the same entity. The American Thoracic Society/European Respiratory Society guidelines provide a useful framework for recognising the progressive behaviour of individual ILDs. Nevertheless, sometimes the "one-size-fits-all" approach to PPF may not lead to the best management decisions for individual patients. Real-life clinical practice presents multiple hurdles for practising clinicians and it is of utmost importance to target early those individuals that will benefit from antifibrotic treatment. This review aims to highlight several clinical points and suggest that, in certain cases, the strict rule of initiating antifibrotic treatment only upon disease progression may warrant some flexibility, particularly in the context of everyday clinical practice. Emphasis is placed on critically examining the criteria used to define progression across different ILDs, commenting on clinical issues such as disease severity at baseline, prevention of acute exacerbations, the definition of "standard treatment", the need for early access to appropriate treatment, prediction of progression, personalised medicine and an aetiologic approach. Engaging technology and artificial intelligence will play a role in the future. Until then, the best possible management decisions will rely on the judgment of treating clinicians, guided by existing evidence and patient needs.

PMID:40769536 | DOI:10.1183/16000617.0023-2025

Autoimmun Rev. 2025 Aug 4:103900. doi: 10.1016/j.autrev.2025.103900. Online ahead of print.

ABSTRACT

Autoimmune connective tissue disease associated with interstitial lung disease (CTD-ILD) includes rheumatoid arthritis-associated ILD, systemic sclerosis-associated-ILD, and several other ILDs. Many patients with CTD-ILD-as well as individuals with other ILDs-develop a progressive pulmonary fibrosis (PPF) similar to idiopathic pulmonary fibrosis (IPF). PPF is characterized by worsening respiratory symptoms, declining lung function despite current pharmacotherapies, and ultimately early death. Current pharmacotherapies for CTD-ILD and PPF include glucocorticoids, immunosuppressants, and anti-fibrotic agents. Due to the scarcity of randomized clinical trials for CTD-ILD, many pharmacotherapies are generally administered off-label (although several are approved in Japan), with notable exceptions including nintedanib, an anti-fibrotic agent approved for SSc-ILD and chronic progressive fibrosing ILD in several countries. As the available agents only slow the decline of pulmonary function and are associated with treatment-limiting side effects, there is a need for more efficacious and tolerable pharmacotherapies for CTD-ILD and PPF. Promising compounds in clinical trials include nerandomilast (a preferential phosphodiesterase 4B inhibitor), admilparant (a lysophosphatidic acid receptor 1 antagonist), and inhaled treprostinil (a prostacyclin analogue). Nerandomilast may have both anti-fibrotic and immunomodulatory properties; in preclinical models of PPF, it reduced neutrophils and macrophages and down-regulated pro-fibrotic signaling pathways. Hopefully, therefore, this pipeline will produce new medications to ease the collectively large burden of CTD-ILD and PPF.

PMID:40769405 | DOI:10.1016/j.autrev.2025.103900

Eur J Med Chem. 2025 Jul 31;298:118013. doi: 10.1016/j.ejmech.2025.118013. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive multifactorial lung disorder characterized by excessive deposition of fibrotic connective tissue. The activation of farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor δ (PPARδ) demonstrated therapeutic efficacy in reducing fibrotic pathology, respectively, suggesting that dual FXR/PPARδ up-regulators may provide a prospective approach to address the polypharmacy dilemma in fibrotic diseases. Herein, the identification campaign of 6-(piperazin-1-yl)imidazo[1,2-b]pyridazine derivatives as FXR/PPARδ dual agonists was described through hybridation of FXR agonist GW-4064 and PPARδ agonist GW-0742. The following exhaustive in vitro FXR and PPARδ activation studies culminated in the optimization of compound 10g, which displayed potent dual-target activities with an FXR agonistic EC50 of 12.28 nM and 69 % PPARδ activation at 100 nM. In a Bleomycin-induced murine in vivo pulmonary fibrosis model, 10g (40 mg/kg, QD) significantly attenuated collagen deposition and reduced the expression of α-SMA in lung tissue. Taken together, these results shed new light on the discovery of novel FXR/PPARδ agonists for the treatment of IPF.

PMID:40768861 | DOI:10.1016/j.ejmech.2025.118013

Am J Physiol Cell Physiol. 2025 Aug 6. doi: 10.1152/ajpcell.00140.2025. Online ahead of print.

ABSTRACT

Pulmonary fibrosis, a life-threatening respiratory condition affecting millions globally, is characterized by progressive lung scarring that severely compromises respiratory function. With few effective treatment options available, it carries a poor prognosis for those affected. Disrupted iron homeostasis is increasingly implicated in its pathogenesis, yet the precise mechanisms linking iron overload to fibrotic progression remain elusive. This study unveils a novel pathway by which iron accumulation orchestrates fibrotic remodeling via secreted phosphoprotein 1 (SPP1)-mediated reprogramming of alveolar type 2 (AT2) cells. Using an integrated approach combining analysis of public single-cell and single-nucleus RNA sequencing datasets with functional validation across multiple murine models of pulmonary fibrosis (iron-induced, bleomycin-induced, and silica-induced), we demonstrate that iron overload within AT2 cells triggers a coordinated transcriptional cascade affecting iron handling, immune cell recruitment, and cellular differentiation. Mechanistically, SPP1 emerges as a key mediator, functioning both externally as a paracrine signal for macrophage recruitment following iron-induced secretion from AT2 cells, and internally as a driver of pathological epithelial transitions, specifically fostering the development of a Krt8+ alveolar intermediate phenotype. The clinical relevance of these findings is substantiated by analysis of human idiopathic pulmonary fibrosis specimens using publicly available single-cell and spatial transcriptomic datasets. These analyses reveal conserved pathway activation and a distinctive spatial organization of SPP1-expressing AT2 cells within remodeled tissue microenvironments, notably in close proximity to macrophages. By establishing SPP1 as a critical nexus between iron dysregulation and fibrotic progression, our work identifies the SPP1 signaling axis as a compelling therapeutic target for this devastating condition.

PMID:40767540 | DOI:10.1152/ajpcell.00140.2025

Stem Cell Res Ther. 2025 Aug 5;16(1):426. doi: 10.1186/s13287-025-04507-y.

ABSTRACT

BACKGROUND: Extracellular Vesicles (EVs) derived from mesenchymal stem cells (MSCs) have gained recognition as promising therapeutic and drug delivery agents in regenerative medicine. However, their clinical application is limited by donor variability, low scalability, and inconsistent therapeutic quality. To overcome these challenges, a robust and standardized production platform is urgently needed.

METHODS: We developed a scalable biomanufacturing strategy by generating and expanding MSCs from extended pluripotent stem cells (EPSC) using a suspension bioreactor culture system. A fixed-bed bioreactor was integrated for automated, continuous expansion of iMSCs and downstream EV harvesting. EVs were isolated through a streamlined protocol and characterized for size, morphology, surface markers, and bioactivity. Therapeutic efficacy was assessed in a bleomycin-induced pulmonary fibrosis mouse model.

RESULTS: iMSC-derived EVs (iMSC-EVs) exhibited comparable characteristics to primary MSC-EVs, including a size distribution of 70-80 nm, cup-shaped morphology, and expression of canonical EV markers (CD63, CD81, TSG101). iMSCs were expanded for up to 20 days in 3D culture, yielding > 5 × 10⁸ cells per batch using a suspension bioreactor culture system and producing ~ 1.2 × 10¹³ EV particles/day in a fixed-bed bioreactor. In vivo, iMSC-EVs significantly reduced Ashcroft fibrosis scores and bronchoalveolar lavage fluid protein levels in bleomycin-injured lungs, with therapeutic efficacy comparable to primary MSC-EVs.

CONCLUSIONS: This study establishes a scalable and standardized platform for producing high-quality iMSC-EVs using bioreactor-based systems. Our approach addresses key limitations in traditional EV production and sets the stage for AI-integrated, fully automated, GMP-compliant manufacturing of therapeutic EVs suitable for clinical translation.

PMID:40765003 | DOI:10.1186/s13287-025-04507-y

Comput Biol Med. 2025 Aug 4;196(Pt B):110867. doi: 10.1016/j.compbiomed.2025.110867. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a degenerative pulmonary condition marked by a substantial accumulation of extracellular matrix and chronic inflammation. Matrix metalloproteinase-7 (MMP-7) is integral to fibrosis and likely a curative focus. This study investigates the therapeutic potential of Tylophora indica (T. indica) plant extract for treating IPF, utilizing in vivo and in silico approaches that target MMP-7.

METHODS AND MATERIALS: T. indica extract was administered to a bleomycin-induced IPF mouse model at 200 and 300 mg/kg/day doses. Efficacy was evaluated through histological analysis and quantitative RT-PCR to measure MMP-7 expression. In silico molecular dynamics simulation and molecular docking identified bioactive compounds from T. indica that could inhibit MMP-7. ADMET profiling was used to evaluate these substances' pharmacological potential and safety.

RESULTS: T. indica extract at 300 mg/kg/day significantly reduced fibrosis and inflammation, improving histopathological scores and lowering MMP-7 expression. In silico analysis identified pergularinine, tylophorine, quercetin, kaempferol, and tylophorinidine as potent MMP-7 inhibitors with stronger binding affinities than pirfenidone, a standard anti-fibrotic drug. Molecular dynamics simulations confirmed the stability of these interactions, and the compounds showed favorable safety profiles in ADMET assessments.

CONCLUSION: T. indica extract demonstrated significant antifibrotic activity by downregulating MMP-7 expression and improving lung histopathology in the IPF mouse model. The identified phytochemicals show strong potential as natural MMP-7 inhibitors, suggesting T. indica as a prospective therapeutic agent for IPF. Additional clinical studies are required to validate these results.

PMID:40763678 | DOI:10.1016/j.compbiomed.2025.110867

Nat Commun. 2025 Aug 4;16(1):7150. doi: 10.1038/s41467-025-61880-1.

ABSTRACT

Healthy alveolar repair relies on the ability of alveolar stem cells to differentiate into specialized epithelial cells for gas exchange. In chronic fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF), this regenerative process is abnormal but the underlying mechanisms remain unclear. Here, using human lung tissue that represents different stages of disease and a 33-plex single-cell imaging mass cytometry (IMC), we present a high-resolution, temporo-spatial cell atlas of the regenerating alveolar niche. With unbiased mathematical methods which quantify statistically enriched interactions, CD206himacrophage subtype and an alveolar basal intermediate epithelial cell emerge as the most statistically robust spatial association in the epithelial and immune cell interactome, found across all stages of disease. Spatially resolved receptor-ligand analysis further offers an in silico mechanism by which these macrophages may influence epithelial regeneration. These findings provide a foundational step toward understanding immune-epithelial dynamics in aberrant alveolar regeneration in IPF.

PMID:40759629 | DOI:10.1038/s41467-025-61880-1

Cureus. 2025 Jul 4;17(7):e87264. doi: 10.7759/cureus.87264. eCollection 2025 Jul.

ABSTRACT

Hypereosinophilic syndrome (HES) is a rare condition characterized by persistent eosinophilia (eosinophil count ≥1.5 × 109/L) and end-organ damage in the absence of an identifiable cause. Cardiac involvement is common and may lead to life-threatening complications. Cystic fibrosis (CF) is a chronic multisystem disease predominantly associated with neutrophilic inflammation, and eosinophilic disorders are less often reported in this population. A 32-year-old woman with CF, complicated by CF-related diabetes and pancreatic insufficiency, presented with chest pain and peripheral eosinophilia (3.2 × 10⁹/L); infectious, autoimmune, and allergic evaluations were negative. Imaging revealed perimyocarditis, and systemic corticosteroids were initially effective but discontinued due to cushingoid side effects and anasarca. She subsequently experienced a recurrence of chest pain accompanied by eosinophilia (1.7 × 10⁹/L), and a diagnosis of idiopathic HES was made based on persistent eosinophilia, cardiac involvement, and exclusion of secondary causes. She responded favorably to monthly subcutaneous mepolizumab, a monoclonal antibody that prevents interleukin-5 (IL-5) from binding to its receptor, thereby inhibiting the recruitment and activation of eosinophils, with resolution of eosinophilia and improvement in symptoms. This case underscores the importance of considering HES in CF patients presenting with unexplained eosinophilia and extrapulmonary symptoms. It also illustrates the efficacy of targeted biologic therapy in managing idiopathic HES when corticosteroids are poorly tolerated.

PMID:40755600 | PMC:PMC12318349 | DOI:10.7759/cureus.87264

Expert Rev Clin Immunol. 2025 Aug 3. doi: 10.1080/1744666X.2025.2543473. Online ahead of print.

ABSTRACT

INTRODUCTION: This network meta-analysis (NMA) of randomized controlled trials (RCTs) aimed to evaluate the efficacy and safety of pharmacotherapies for progressive fibrotic-interstitial lung diseases (PF-ILDs) to identify optimal treatments.

METHODS: We searched for RCTs on PF-ILD [idiopathic pulmonary fibrosis (IPF), connective tissue disease-ILD (CTD-ILD), chronic hypersensitivity pneumonitis (CHP), and pulmonary sarcoidosis] pharmacotherapies until 5 June 2025. NMA assessed efficacy [forced vital capacity, diffusing capacity of lungs for carbon monoxide, 6-minute-walk distance] and safety [serious adverse events (SAEs) and all-cause mortality] (PROSPERO: CRD42024554475).

RESULTS: We included sixty-five studies (13,521 participants) for forty-eight drugs in IPF, ten studies (1,508 participants) for eight drugs in CTD-ILD, four studies (259 participants) for three drugs in CHP, and nine studies (525 participants) for nine drugs in pulmonary sarcoidosis. In IPF, pirfenidone, nintedanib, and IFNγ-1b slowed lung function decline and reduced mortality. In CTD-ILD, pirfenidone, nintedanib, tocilizumab, and cyclophosphamide improved lung function and reduced mortality, with higher SAEs for nintedanib and cyclophosphamide. Pirfenidone and prednisolone benefited CHP, while budesonide improved lung function in pulmonary sarcoidosis.

CONCLUSIONS: Anti-fibrotic drugs - Pirfenidone and nintedanib effectively slow disease progression and reduce mortality in PF-ILDs. Emerging therapies like IFNγ-1b warrant further research, underscoring the need for large, high-quality RCTs.

PMID:40754799 | DOI:10.1080/1744666X.2025.2543473