BMJ Case Rep. 2025 Mar 3;18(3):e263966. doi: 10.1136/bcr-2024-263966.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fibrosing pneumonia of unknown causation with a chronic, progressive course that may be modified by treatment with the antifibrotic agents, pirfenidone and nintedanib. Both drugs have been shown to slow disease progression, but, in rare cases, pirfenidone has been shown to stabilise and even improve lung function. We present a case of a patient whose lung function and pathognomonic features on CT imaging improved significantly on commencement of treatment with pirfenidone. Withholding pirfenidone was associated with a functional and morphological deterioration on imaging that subsequently reversed and stabilised following recommencement of this treatment. We discuss potential mechanisms that might explain this treatment response, compare our case to others described previously and the potential consequences that restricted prescribing within a specified range of vital capacity may have on the opportunity to influence the natural history of IPF early before irreversible fibrosis develops.

PMID:40032576 | DOI:10.1136/bcr-2024-263966

bioRxiv [Preprint]. 2025 Feb 17:2025.02.12.637970. doi: 10.1101/2025.02.12.637970.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by tissue scarring that disrupts gas exchange. Epithelial cell dysfunction, fibroblast activation, and excessive extracellular matrix deposition drive this pathology that ultimately leads to respiratory failure. Mechanistic studies have shown that repeated injury to alveolar epithelial cells initiates an aberrant wound-healing response in surrounding fibroblasts through secretion of mediators like transforming growth factor-β, yet the precise biological pathways contributing to disease progression are not fully understood. To better study these interactions there is a critical need for lung models that replicate the cellular heterogeneity, geometry, and biomechanics of the distal lung microenvironment. In this study, induced pluripotent stem cell-derived alveolar epithelial type II (iATII) cells and human pulmonary fibroblasts were arranged to replicate human lung micro-architecture and embedded in soft or stiff poly(ethylene glycol) norbornene (PEG-NB) hydrogels that recapitulated the mechanical properties of healthy and fibrotic lung tissue, respectively. The co-cultured cells were then exposed to pro-fibrotic biochemical cues, including inflammatory cytokines and growth factors. iATIIs and fibroblasts exhibited differentiation pathways and gene expression patterns consistent with trends observed during IPF progression in vivo . A design of experiments statistical analysis identified stiff hydrogels combined with pro-fibrotic biochemical cue exposure as the most effective condition for modeling fibrosis in vitro . Finally, treatment with Nintedanib, one of only two Food and Drug Administration (FDA)-approved drugs for IPF, was assessed. Treatment reduced fibroblast activation, as indicated by downregulation of key activation genes, and upregulated several epithelial genes. These findings demonstrate that human 3D co-culture models hold tremendous potential for advancing our understanding of IPF and identifying novel therapeutic targets.

STATEMENT OF SIGNIFICANCE: This study leverages advanced biomaterials and biofabrication techniques to engineer physiologically relevant, patient-specific, and sex-matched models of pulmonary fibrosis, addressing the critical need for pre-clinical therapeutic drug screening platforms. These human 3D lung models successfully replicated key features of fibrotic lung tissue. Tuning microenvironmental stiffness of 3D PEG-NB hydrogels to match fibrotic lung values and exposing human iATII cells and fibroblasts to pro-inflammatory biochemical cues recreated hallmark characteristics of in vivo fibrosis pathogenesis, including epithelial differentiation and loss, as well as fibroblast activation. The utility of these models was further validated by demonstrating responsiveness to Nintedanib, a clinically available treatment for IPF. These findings highlight the transformative potential of well-defined biomaterial-based 3D models for elucidating complex disease mechanisms and accelerating therapeutic drug discovery for chronic pulmonary diseases like idiopathic pulmonary fibrosis.

PMID:40027659 | PMC:PMC11870410 | DOI:10.1101/2025.02.12.637970

SLAS Discov. 2025 Feb 28:100223. doi: 10.1016/j.slasd.2025.100223. Online ahead of print.

ABSTRACT

Senescent cells contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease with significant unmet need and therefore, there is an interest in discovering new drug targets that regulate this process. We design and perform a phenotypic screen with a secreted protein library in primary human lung fibroblasts to identify modulators of cell senescence. We identify FGF9 as a suppressor of several senescence phenotypes reducing stimulated p21 expression, enlarged morphology, DNA damage and SASP secretion, which is consistent with both DNA-damage and ROS induced senescence. We also show that FGF9 reduces fibroblast activation in both healthy and IPF fibroblasts shown by a reduction in pro-fibrotic markers such as α-smooth muscle actin and COL1A1 mRNA. Our findings identify FGF9 as a suppressor of both senescence and fibrotic features in lung fibroblasts and therefore could be targeted as a new therapeutic strategy for respiratory diseases such as IPF.

PMID:40024445 | DOI:10.1016/j.slasd.2025.100223

Int J Biol Macromol. 2025 Feb 28:141602. doi: 10.1016/j.ijbiomac.2025.141602. Online ahead of print.

ABSTRACT

BACKGROUND: SARS-CoV-2 disrupts lung vascular endothelial integrity, contributing to severe COVID-19 complications. However, the molecular mechanisms driving endothelial dysfunction remain underexplored, and targeted therapeutic strategies are lacking.

OBJECTIVE: This study investigates Naringenin-7-O-glucoside (N7G) as a multi-target therapeutic candidate for modulating vascular integrity and immune response by inhibiting MMP1, MMP7, and SERPINE1-key regulators of extracellular matrix (ECM) remodeling and inflammation.

METHODS & RESULTS: RNA-set analysis of COVID-19 lung tissues identified 17 upregulated N7G targets, including MMP1, MMP7, and SERPINE1, with the latter exhibiting the highest expression. PPI network analysis linked these targets to ECM degradation, IL-17, HIF-1, and AGE-RAGE signaling pathways, and endothelial dysfunction. Disease enrichment associated these genes with idiopathic pulmonary fibrosis and asthma. Molecular docking, 200 ns MD simulations (triplicate), and MMGBSA calculations confirmed N7G's stable binding affinity to MMP1, MMP7, and SERPINE1. Immune profiling revealed increased neutrophils and activated CD4+ T cells, alongside reduced mast cells, NK cells, and naïve B cells, indicating immune dysregulation. Correlation analysis linked MMP1, MMP7, and SERPINE1 to distinct immune cell populations, supporting N7G's immunomodulatory role.

CONCLUSION: These findings suggest that N7G exhibits multi-target therapeutic potential by modulating vascular integrity, ECM remodeling, and immune dysregulation, positioning it as a promising candidate for mitigating COVID-19-associated endothelial dysfunction.

PMID:40024412 | DOI:10.1016/j.ijbiomac.2025.141602

Phytomedicine. 2025 Mar 1;140:156545. doi: 10.1016/j.phymed.2025.156545. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an irreversible lung disease for which there is a lack of effective and safe therapeutic drugs. 13-Methylpalmatine (13-Me-PLT) is an active compound from Coptis chinensis, and no study has yet been reported on its pharmacological effects in pulmonary fibrotic diseases. The group has previously demonstrated the antimyocardial fibrosis efficacy of 13-Me-PLT but its effect on pulmonary fibrosis and its potential mechanism has not yet been investigated.

PURPOSE: The present research is designed to clarify the therapeutic potential and mechanism of action of 13-Me-PLT in IPF using a bleomycin (BLM)-induced mouse model of IPF.

METHODS: In vivo, mice were administrated with BLM to establish the IPF model, and IPF mice were treated with 13-Me-PLT (5, 10, and 20 mg/kg) and pirfenidone (PFD, 300 mg/kg) by gavage. In vitro, we employed TGF-β1 (10 ng/ml)-induced MRC5 cells, which were then treated with 13-Me-PLT (5, 10, 20 μM) and PFD (500 μM). High-throughput transcriptome sequencing, molecular dynamics simulations, molecular docking and Surface plasmon resonance (SPR) were employed to elucidate the underlying mechanisms of 13-Me-PLT in mitigating IPF.

RESULT: In vivo experiments showed that 13-Me-PLT significantly ameliorated BLM-induced lung fibrosis in mice. In vitro studies, 13-Me-PLT showed good antifibrotic potential by inhibiting fibroblast differentiation. Transcriptomic analysis of mouse lung tissues identified ITGA5 and TGF-β/Smad signaling pathways as key targets for the antifibrotic effects of 13-Me-PLT. Molecular docking and kinetic analyses further supported these findings. Functional studies involving ITGA5 silencing and overexpression confirmed that 13-Me-PLT down-regulated ITGA5 expression and inhibited the activation of the TGF-β/Smad signaling pathway, confirming its mechanism of action.

CONCLUSION: To our best knowledge, these results provide the first insight that 13-Me-PLT is protective against BLM-induced IPF in mice. Unlike existing antifibrotic drugs, 13-Me-PLT specifically targets the ITGA5/TGF-β/Smad signaling pathway, offering a novel and potentially more effective therapeutic approach. This study not only validates the antifibrotic efficacy of 13-Me-PLT but also elucidates its unique mechanism of action, these findings may provide an opportunity to develop new drugs to treat IPF.

PMID:40023972 | DOI:10.1016/j.phymed.2025.156545

Rev Mal Respir. 2025 Feb 28:S0761-8425(25)00050-6. doi: 10.1016/j.rmr.2025.02.007. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare, progressive and fatal disease without pharmacologic curative treatments for the patients. TGF-β is a crucial cytokine in the fibrotic process, and its intracellular signaling pathways are complex and rely on the activation of its receptor. This review summarizes our knowledge on the regulatory checkpoints of the TGF-β signaling. In addition, the main strategies and key potential therapeutic targets identified over recent years are presented, with particular emphasis laid on how they can be used to develop new treatments for pulmonary fibrosis.

PMID:40023715 | DOI:10.1016/j.rmr.2025.02.007

Respir Res. 2025 Feb 28;26(1):81. doi: 10.1186/s12931-025-03146-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are interstitial lung diseases (ILD) that carry a high burden and mortality. IPF/PPF experts and patients call for standardized care, outcome harmonization and holistic management in these complex and devastating diseases, with a focus on person-centeredness. In this cross-sectional international survey study, we aimed to gather information on the person-centred health outcomes European healthcare professionals (HCPs) already use or deem important for use in routine care for IPF/PPF. This work is part of the COCOS-IPF project on developing a Core Outcome Set (COS) for and with patients with IPF/PPF.

METHODS: With the input of IPF/PPF experts, psychologists and patients, we developed an online survey for European multidisciplinary HCPs with IPF/PPF expertise. The survey was programmed in QualtricsXM, piloted and distributed via the networks of the COCOS-IPF consortium. We used content analysis to create an overall list of outcome domains mentioned in the survey, classified these according to the COMET (Core Outcome Measures in Effectiveness Trials) taxonomy and calculated the frequency of all outcomes mentioned.

RESULTS: A total of 149 experts, mainly pulmonologists (n = 120, 81%) working in ILD expert centres, from 31 European countries participated. Of the 40 different outcome domains mentioned, the majority referred to `physiological/clinical` (n = 773, 81%) and `life impact` (n = 138, 14%) outcome domains. Of these, `lung function' (n = 280, 29%), 'exercise capacity' (n = 123, 13%) and `quality of life` (n = 103, 11%) were reported as most frequently used person-centred health outcomes. Survey respondents deemed the same three outcome domains the most important for use in the routine clinical IPF/PPF care, supplemented by chest symptoms. Pulmonologists reported mainly about routine use of `lung function` (n = 252, 26%), while allied HCPs put more focus on outcomes related to physical condition and whole body status.

CONCLUSIONS: HCPs have identified 40 different outcomes domains in a European multidisciplinary survey on person-centred health outcomes in IPF/PPF. Lung function, exercise capacity, quality of life and chest symptoms were rated as the most relevant health outcomes to be assessed routinely in clinical care. These insights can help to support the development of a COS for IPF/PPF clinical care.

PMID:40022111 | DOI:10.1186/s12931-025-03146-4

Respir Res. 2025 Feb 28;26(1):80. doi: 10.1186/s12931-025-03139-3.

ABSTRACT

BACKGROUND: Supplemental oxygen therapy is commonly prescribed in clinical practice for patients with fibrosing interstitial lung disease (ILD) to reduce breathlessness and increase physical capacity. Only a few studies have evaluated the incidence of oxygen therapy use, with evidence lacking in its use among fibrosing ILD subtypes including patients with idiopathic pulmonary fibrosis (IPF) and non-IPF ILD. This study aimed to estimate incidence of oxygen therapy and factors associated with oxygen therapy initiation.

METHODS: This non-interventional study used US administrative claims and electronic health record data from 01 October 2015 to 30 June 2022. Patients aged ≥ 18 years with newly diagnosed fibrosing ILD (≥ 2 fibrosing ILD diagnoses in any position on different dates of service within 365 days) were included; the index date was the first date with ILD diagnosis. Patients were followed until the earlier of health plan disenrollment, death, or end of study period. Oxygen therapy use was evaluated among patients without evidence of oxygen therapy before the index date, stratified by the underlying fibrosing disease (i.e., IPF vs. non-IPF ILD). Factors associated with oxygen therapy use were evaluated using Cox proportional hazards regression.

RESULTS: A total of 114,921 patients (IPF n = 5,555; non-IPF ILD n = 109,366) newly diagnosed with fibrosing ILD were included in the study. The mean (standard deviation) age of patients with ILD was 66.9 (14.2) years, and 47.2% were male. Patients were followed for a mean of 24 months after ILD diagnosis, during which 38% of fibrosing ILD patients initiated oxygen therapy; a higher proportion of patients with IPF initiated oxygen therapy compared to those with non-IPF ILD (68% and 36%, respectively). Factors associated with oxygen therapy initiation included IPF, higher Charlson comorbidity scores, and comorbidities that impair respiratory capacity.

CONCLUSIONS: The study findings demonstrate a substantial proportion of patients with fibrosing ILD initiated oxygen therapy following initial ILD diagnosis, with higher rates of oxygen therapy initiation observed among patients with IPF compared with non-IPF ILD. Respiratory comorbidities were key factors associated with increased initiation of oxygen therapy.

PMID:40022082 | DOI:10.1186/s12931-025-03139-3

Respir Res. 2025 Feb 28;26(1):73. doi: 10.1186/s12931-025-03136-6.

ABSTRACT

BACKGROUND: The prognostic value of patterns and quantitative measures of lung fibrosis on high-resolution computed tomography (HRCT) in patients identified as having progressive pulmonary fibrosis (PPF) has not been established. We investigated whether HRCT patterns and quantitative scores were associated with risk of progression in patients with PPF.

METHODS: Patients enrolled in the ILD-PRO Registry had an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis, reticular abnormality and traction bronchiectasis, and met criteria for ILD progression. HRCT images taken between 24 months prior to enrollment and 90 days after enrollment were analyzed using a machine learning algorithm to derive quantitative scores. Associations were assessed between HRCT pattern (usual interstitial pneumonia [UIP]-like versus other patterns) and tertiles of quantitative scores and measures of disease severity at enrollment, and between these patterns/tertiles at enrollment and ILD progression (relative decline in forced vital capacity [FVC] % predicted ≥ 10%, lung transplant, or death) over a median follow-up of 17.3 months.

RESULTS: Among 395 patients, 178 (45.1%) had a UIP-like pattern on HRCT. A UIP-like pattern did not associate with worse disease severity at enrollment or an increased risk of ILD progression (HR 1.01 [95% CI: 0.71, 1.44]). The highest quantitative lung fibrosis (QLF) score tertile (≥ 20.5%) was associated with worse disease severity. In unadjusted analyses, patients with QLF scores in the highest tertile had a significantly increased risk of ILD progression versus the middle tertile (HR [95% CI] 1.63 [1.07, 2.49] and a numerically increased risk versus the lowest tertile (HR 1.46 [0.97, 2.18]); however, after adjustment for sex, age, FVC % predicted and oxygen use at enrollment, there were no significant differences. There were no significant associations between tertiles of quantitative ILD score, quantitative ground glass score, or quantitative honeycomb cysts score and risk of ILD progression in unadjusted or adjusted analyses.

CONCLUSIONS: In a real-world cohort of patients with PPF, QLF score associated with subsequent risk of ILD progression, while HRCT pattern did not. The QLF score did not provide additional prognostic information beyond clinical variables.

TRIAL REGISTRATION: ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.

CLINICALTRIALS: gov .

PMID:40022059 | DOI:10.1186/s12931-025-03136-6

BMC Pulm Med. 2025 Feb 28;25(1):98. doi: 10.1186/s12890-025-03555-7.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, and fatal disease characterized by progressive interstitial lung fibrosis. Given its insidious onset and poor outcome, there is an urgent need to elucidate the molecular mechanisms underlying IPF and identify effective therapeutic targets and diagnosis and prognosis biomarkers. Ferroptosis is an iron-dependent form of programmed cell death that occurs as lipid peroxides accumulate. Growing evidence suggests that ferroptosis is important in IPF.

METHODS: Human ferroptosis PCR array was performed on IPF and control lung tissue. The differentially expressed ferroptosis-related genes (DE-FRGs) were identified, underwent functional enrichment analyses, protein-protein interaction network construction, and potential drug target prediction. The DE-FRGs were validated and their value as diagnostic and prognostic blood biomarkers were evaluated using the Gene Expression Omnibus dataset GSE28042.

RESULTS: The array identified 13 DE-FRGs. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the DE-FRGs were mainly related to iron ion transport, blood microparticles, and oxidoreductase activity, and were involved in porphyrin metabolism, necroptosis, and the p53 signaling pathway in addition to ferroptosis. The 13 DE-FRGs were analyzed using the Drug-Gene Interaction Database to explore novel IPF therapeutic agents, yielding 42 potential drugs. Four DE-FRGs (BBC3, STEAP3, EPRS, SLC39A8) in the peripheral blood of IPF patients from the GSE28042 dataset demonstrated the same expression pattern as that observed in the lung tissue array. The receiver operating characteristic analysis demonstrated that the area under the curve of STEAP3 and EPRS were > 0.75. The survival analysis demonstrated that STEAP3 and EPRS were significantly different between the IPF and control groups.

CONCLUSIONS: The FRG expression profiles in IPF and control lung tissue were characterized. The findings provided valuable ideas to elucidate the role of ferroptosis in IPF and aided the identification of novel IPF therapeutic targets and biomarkers.

PMID:40022042 | DOI:10.1186/s12890-025-03555-7

Chest. 2025 Feb 26:S0012-3692(25)00267-3. doi: 10.1016/j.chest.2025.02.018. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease associated with lung function decline and high mortality.

RESEARCH QUESTION: What are the associations between thresholds of lung function decline and the risk of mortality in patients with IPF?

STUDY DESIGN AND METHODS: The Idiopathic Pulmonary Fibrosis-Prospective Outcomes Registry enrolled patients with IPF that was diagnosed or confirmed at the enrolling center within the prior 6 months. Associations between time to first decline in FVC or diffusing capacity of the lungs for carbon monoxide (Dlco) of ≥ 2% predicted, ≥ 5% predicted, and ≥ 10% predicted (and ≥ 15% predicted for Dlco) and risk of subsequent death or lung transplant was assessed using Cox proportional hazards models with a time-dependent covariate. Models were unadjusted or adjusted for FVC and Dlco % predicted, age, sex, smoking status, BMI, antifibrotic treatment (yes or no), and oxygen use at enrollment.

RESULTS: Among 1,001 patients, median follow-up time was 38.4 months. Significant associations were observed between all thresholds of decline in FVC and Dlco % predicted and the risk of death or lung transplant in unadjusted and adjusted analyses. In adjusted analyses, absolute declines in FVC of ≥ 2% predicted, ≥ 5% predicted, and ≥ 10% predicted were associated with 1.8-fold, 2.3-fold, and 2.7-fold increases in the risk of subsequent death or lung transplant, whereas absolute declines in Dlco of ≥ 2% predicted, ≥ 5% predicted, ≥ 10% predicted, and ≥ 15% predicted were associated with 2.0-fold, 1.4-fold, 1.5-fold, and 1.9-fold increases in the risk of subsequent death or lung transplantation, respectively. For Dlco, but not FVC, the increase in risk generally was greater for patients meeting a threshold based on a relative rather than an absolute decline.

INTERPRETATION: Even small declines in FVC and Dlco % predicted inform prognosis in patients with IPF.

PMID:40020995 | DOI:10.1016/j.chest.2025.02.018

Chem Biomed Imaging. 2025 Jan 17;3(2):85-94. doi: 10.1021/cbmi.4c00065. eCollection 2025 Feb 24.

ABSTRACT

Disease-recapitulating animal models are valuable tools in preclinical development for the study of compounds. In the case of fibrotic pulmonary diseases such as idiopathic pulmonary fibrosis (IPF), the bleomycin model of lung injury in the mouse is widely used. To evaluate bleomycin-induced changes in the lung, we employed a quantitative, multimodal approach. Using in vivo microcomputed tomography (μCT), we demonstrated radiographic changes associated with disease progression in aeration levels of the lung parenchyma. There exists an unmet need for a quantitative, high-resolution imaging probe to detect pulmonary fibrosis, particularly that can differentiate between inflammatory and fibrotic components of the disease. Matrix remodeling and overexpression of extracellular matrix (ECM) proteins such as collagen and fibronectin are hallmarks of organ fibrosis. A splice variant of fibronectin containing extra domain A (FnEDA) is of particular interest in fibrosis due to its high level of expression in diseased tissue, which is confirmed here using immunohistochemistry (IHC) in mouse and human lungs. An antibody against FnEDA was evaluated for use as an imaging tool, particularly by using in vivo single-photon emission computed tomography (SPECT) and ex vivo near-infrared (NIR) fluorescence imaging. These data were further corroborated with histological tissue staining and fibrosis quantitation based on a Modified Ashcroft (MA) score and a digital image analysis of whole slide lung tissue sections. The fusion of these different approaches represents a robust integrated workflow combining anatomical and molecular imaging technologies to enable the visualization and quantitation of disease activity and treatment response with an inhibitor of the TGFβ signaling pathway.

PMID:40018646 | PMC:PMC11863149 | DOI:10.1021/cbmi.4c00065

Eur Respir J. 2025 Feb 27;65(2):2402224. doi: 10.1183/13993003.02224-2024. Print 2025 Feb.

NO ABSTRACT

PMID:40015735 | DOI:10.1183/13993003.02224-2024

Biogerontology. 2025 Feb 26;26(2):64. doi: 10.1007/s10522-025-10208-z.

ABSTRACT

Cellular senescence and hypoxia-inducible factor (HIF) signaling are crucial in pulmonary aging and age-related lung diseases such as chronic obstructive pulmonary disease idiopathic pulmonary fibrosis and lung cancer. HIF plays a pivotal role in cellular adaptation to hypoxia, regulating processes like angiogenesis, metabolism, and inflammation. Meanwhile, cellular senescence leads to irreversible cell cycle arrest, triggering the senescence-associated secretory phenotype which contributes to chronic inflammation, tissue remodeling, and fibrosis. Dysregulation of these pathways accelerates lung aging and disease progression by promoting oxidative stress, mitochondrial dysfunction, and epigenetic alterations. Recent studies indicate that HIF and senescence interact at multiple levels, where HIF can both induce and suppress senescence, depending on cellular conditions. While transient HIF activation supports tissue repair and stress resistance, chronic dysregulation exacerbates pulmonary pathologies. Furthermore, emerging evidence suggests that targeting HIF and senescence pathways could offer new therapeutic strategies to mitigate age-related lung diseases. This review explores the intricate crosstalk between these mechanisms, shedding light on how their interplay influences pulmonary aging and disease progression. Additionally, we discuss potential interventions, including senolytic therapies and HIF modulators, that could enhance lung health and longevity.

PMID:40011266 | DOI:10.1007/s10522-025-10208-z

Pulm Pharmacol Ther. 2025 Feb 24:102346. doi: 10.1016/j.pupt.2025.102346. Online ahead of print.

ABSTRACT

BACKGROUND: Baricitinib and nintedanib can target inflammation and fibrosis respectively, which are the two most important processes in idiopathic pulmonary fibrosis (IPF). However, it is still unknown whether targeting these two processes simultaneously can synergistically improve the therapeutic effect of IPF. Therefore, it is necessary to predict the possible translational potential through preclinical studies.

METHODS: We evaluated both the in vitro and in vivo efficacy of a drug combination, nintedanib with baricitinb, a JAK1/JAK2 inhibitor. We first examined the fibroblast proliferation and myofibroblast differentiation of single agents or combinations by the MTT assay. Then we determined the migration of the fibroblasts by a wound healing assay. Meanwhile, we quantified the protein level of related growth factor or cytokines in the cell supernatant by ELISA. Finally, we investigated the therapeutic potential and mechanism in a bleomycin-induced mouse model.

RESULTS: Our results showed that the combination of nintedanib and baricitinib was more effective in suppressing fibroblast proliferation, myofibroblast transformation and fibroblast migration compared to either agent alone. In a bleomycin-induced IPF mouse model, the combination therapy resulted in a higher survival rate, increased body weight, and a lower lung/body weight ratio compared to the individual drugs. Moreover, both drugs improved lung functions in mice, but their combined administration led to superior outcomes. Histopathological analysis also revealed that the combination therapy mitigated pulmonary inflammation and fibrosis to a greater extent than the individual compounds. Mechanistically, baricitinib appears to orchestrate the effects of nintedanib in IPF by modulating the expression of genes such as il-6, tgf-β, col1α1 and fibronectin.

CONCLUSION: The synergistic targeting of inflammation by baricitinib and fibrosis by nintedanib preclinically improves IPF outcomes, thus suggesting their potential as a novel combination therapy for this condition.

PMID:40010629 | DOI:10.1016/j.pupt.2025.102346

Autoimmun Rev. 2025 Feb 24:103782. doi: 10.1016/j.autrev.2025.103782. Online ahead of print.

ABSTRACT

B cells play a key role in the pathophysiology of systemic sclerosis (SSc). While they are less characterized than their circulating counterparts, tissue-infiltrating B cells may have a more direct pathological role in tissues. In this review, we decipher the multiple evidence of B cells infiltration in the skin and lungs of SSc patients and animal models of SSc but also of other chronic fibrotic diseases with similar pathological mechanisms such as chronic graft versus host disease, idiopathic pulmonary fibrosis or morphea. We also recapitulate the current knowledge about mechanisms of B cells infiltration and their functions in tissues. Finally, we discuss B cell targeted therapies, and their specific impact on infiltrated B cells. Understanding the local consequences of infiltrating B cells is an important step for a better management of patients and the improvement of therapies in SSc.

PMID:40010623 | DOI:10.1016/j.autrev.2025.103782

Ther Adv Drug Saf. 2025 Feb 24;16:20420986251321704. doi: 10.1177/20420986251321704. eCollection 2025.

ABSTRACT

Artificial intelligence (AI) is transforming medication research and development, giving clinicians new treatment options. Over the past 30 years, machine learning, deep learning, and neural networks have revolutionized drug design, target identification, and clinical trial predictions. AI has boosted pharmaceutical R&D (research and development) by identifying new therapeutic targets, improving chemical designs, and predicting complicated protein structures. Furthermore, generative AI is accelerating the development and re-engineering of medicinal molecules to cater to both common and rare diseases. Although, to date, no AI-generated medicinal drug has been FDA-approved, HLX-0201 for fragile X syndrome and new molecules for idiopathic pulmonary fibrosis have entered clinical trials. However, AI models are generally considered "black boxes," making their conclusions challenging to understand and limiting the potential due to a lack of model transparency and algorithmic bias. Despite these obstacles, AI-driven drug discovery has substantially reduced development times and costs, expediting the process and financial risks of bringing new medicines to market. In the future, AI is expected to continue to impact pharmaceutical innovation positively, making life-saving drug discoveries faster, more efficient, and more widespread.

PMID:40008227 | PMC:PMC11851753 | DOI:10.1177/20420986251321704

Front Pharmacol. 2025 Feb 11;16:1509665. doi: 10.3389/fphar.2025.1509665. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF), an interstitial lung disease of unknown etiology, remains incurable with current therapies, which fail to halt disease progression or restore lung function. However, Feibi Recipe No. 2 (FBR2), a clinically validated traditional Chinese medicine formula, exhibits potential as an IPF treatment.

OBJECTIVE: This study aimed to investigate the regulatory effect of FBR2 on ferroptosis through the SIRT3/p53 pathway and its therapeutic potential in improving IPF.

METHODS: Pulmonary fibrosis was induced in C57BL/6J mice by intratracheal instillation of Bleomycin (BLM), followed by FBR2 treatment via gavage. Assessments encompassed histopathology, ELISA for cytokine detection, IHC and Western blot for protein expression analysis, and qRT-PCR for gene expression quantification. Transmission electron microscopy (TEM) was used to observe mitochondrial morphology. The roles of Erastin and the SIRT3 inhibitor 3-TYP were also explored to elucidate FBR2's mechanisms of action.

RESULTS: FBR2 treatment significantly mitigated BLM-induced lung injury in mice, as evidenced by improved body weight and survival rates, and reduced levels of inflammatory cytokines, including IL-6 and TNF-α. FBR2 decreased collagen deposition in lung tissue, as shown by Masson's staining and IHC detection of Col-I and α-SMA, confirming its anti-fibrotic effects. It also reduced iron and MDA levels in lung tissue, increased GSH-Px activity, improved mitochondrial morphology, and enhanced the expression of GPX4 and SLC7A11, indicating its ferroptosis-inhibitory capacity. Furthermore, FBR2 increased SIRT3 levels and suppressed p53 and its acetylated forms, promoting the translocation of p53 from the nucleus to the cytoplasm where it co-localized with SIRT3. The protective effects of FBR2 were reversed by Erastin, confirming the central role of ferroptosis in pulmonary fibrosis treatment. The use of 3-TYP further confirmed FBR2's intervention in ferroptosis and cellular senescence through the SIRT3/p53 pathway.

CONCLUSION: FBR2 shows therapeutic potential in a BLM-induced pulmonary fibrosis mouse model, with its effects mediated through modulation of the ferroptosis pathway via the SIRT3/p53 mechanism. This study provides novel evidence for the targeted treatment of IPF and offers further insights into its pathogenesis.

PMID:40008127 | PMC:PMC11850536 | DOI:10.3389/fphar.2025.1509665

Respir Med Case Rep. 2025 Jan 28;54:102168. doi: 10.1016/j.rmcr.2025.102168. eCollection 2025.

ABSTRACT

INTRODUCTION: Nintedanib is a tyrosine kinase inhibitor and has been approved for the treatment of idiopathic pulmonary fibrosis (IPF) since 2020. In Clinical trials, the antifibrotic effect of nintedanib was shown.

CASE: A 60-year-old female medical assistant, infected with COVID-19 in 10/2020, experienced a complicated course of disease leading to tracheal stenosis. Various interventions, including stent placements and tracheal surgeries, were performed. Due to recurrent restenosis, the patient was treated with nintedanib, a tyrosine kinase inhibitor used in idiopathic pulmonary fibrosis. The treatment spanned 306 days, during which the patient showed stability in pulmonary function. Nintedanib demonstrated a potential anti-inflammatory effect, reducing the frequency of interventions and prolonging stent-free intervals. The results suggest possible efficacy of nintedanib in managing scar-related granulation tissue, highlighting its potential in treating tracheal stenosis.

CONCLUSION: This case shows a decreased need for interventions, and the longer duration of stent placement may suggest a potential role for nintedanib in diminishing hypertrophic scarring, possibly through an anti-inflammatory effect. Further exploration of this potential in additional clinical trials would be valuable.

PMID:40007765 | PMC:PMC11849196 | DOI:10.1016/j.rmcr.2025.102168

Bioorg Chem. 2025 Feb 18;157:108294. doi: 10.1016/j.bioorg.2025.108294. Online ahead of print.

ABSTRACT

PDE4 inhibitors have been developed as anti-inflammatory medications primarily used in the clinical treatment of pulmonary inflammations such as asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. However, the application of these drugs is usually restricted by obvious side effects, such as nausea and vomiting. Our previous study found that several natural PDE4 inhibitors or their modified derivatives showed minimal side effects, particularly reduced incidence of nausea and vomiting, which aroused our interest in searching for natural PDE4 inhibitors. In this study, a chemical investigation of an active fraction of Piper betle L. leaves led to the characterization of 23 hydroxychavicol derivatives, including 18 hydroxychavicol-type lignans. Compounds 1-9 were new lignans, with three of them being racemates that were eventually resolved into isolated (+)- and (-)-enantiomers. Compounds 1-5 and 10, neolignans characterized by a dioxane moiety, were unique to this species within the genus Piper. Compounds 5 and 10 were the sole sesquineolignans found in the genus Piper. Compounds 5, 7-14, 16, 17, and 21 exhibited considerable inhibition towards PDE4 with IC50 values ranging from 1.8 to 10 μM, with hit 7 exhibiting remarkable activity (1.8 μM). Further anti-inflammatory assays revealed that compounds 5, 7, 9, and 16 decreased the expression of several key inflammatory mediators in LPS-stimulated RAW 264.7 cells. Notably, 16 was comparable to the positive control rolipram at the same concentration of 10 μM. A primary study of the mechanism of action revealed that 16 may exert anti-inflammatory effect by inhibiting the NF-κB signaling pathway, displaying significant inhibition of the phosphorylation of IκB-α and p65 at concentrations of 5 and 10 μM. These findings suggest that hydroxychavicol derivatives from P. betle L. leaves may serve as new PDE4 inhibitors, offering promising leads for the development of anti-inflammatory medications.

PMID:40007350 | DOI:10.1016/j.bioorg.2025.108294