Pulmonary pharmacology & therapeutics最新文献

{"title":"Experimental modeling of pulmonary fibrosis and combined emphysema in mice using repeated doses of bleomycin and cigarette smoke extract","authors":"Jung Hur ,&nbsp;Chin Kook Rhee ,&nbsp;Joon Young Choi ,&nbsp;Yong Suk Jo","doi":"10.1016/j.pupt.2025.102376","DOIUrl":"10.1016/j.pupt.2025.102376","url":null,"abstract":"<div><h3>Rationale</h3><div>A high prevalence of smoking among idiopathic pulmonary fibrosis (IPF) patients increases the risk of emphysema. Combined pulmonary fibrosis and emphysema (CPFE) occurs predominantly in males, characterized by severe exercise-induced dyspnea, decreased diffusing capacity, and increased lung cancer risk. The exclusion of CPFE patients from clinical studies has limited understanding of its pathophysiology, treatment, and prognosis. This study aimed to close this knowledge gap by comparing CPFE with pure IPF in animal models, with the intent of developing phenotype-directed therapeutic strategies.</div></div><div><h3>Methods</h3><div>Eight-week-old female C57BL/6J mice received biweekly intratracheal bleomycin (BLM, 2 U/kg/100 μL) for 3 doses. For the CPFE model, additional intranasal cigarette smoke extract (CSE) was administered twice weekly. Inflammation and fibrosis were evaluated through bronchoalveolar lavage fluid (BALF), proinflammatory cytokines, fibrosis markers, and lung histology.</div></div><div><h3>Results</h3><div>BALF analysis showed increased cell counts in all BLM-treated groups, primarily macrophages, with elevated interleukin (IL)-6, transforming growth factor (TGF)-β1, and matrix metalloproteinases (MMP 3 and MMP 8). The BLM and CSE treated group displayed higher macrophages and lymphocytes counts than BLM alone. Lung tissue analysis revealed increased hydroxyproline, inflammation scores, Ashcroft scores, and higher α-smooth muscle actin (SMA) and collagen 1 expression in BLM-treated groups. The BLM and CSE treated group demonstrated notably higher emphysema formation as measured by mean linear intercept (MLI).</div></div><div><h3>Conclusions</h3><div>Through repeated BLM administrations and CSE exposure, an effective model for persistent pulmonary fibrosis and emphysema was established, enabling preclinical studies on CPFE and IPF and exploration of phenotype-directed therapeutic strategies for pulmonary fibrosis.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102376"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel macrolide, EP395, with reduced antibacterial activity and an enhancing effect on respiratory epithelial barrier","authors":"Thorarinn Gudjonsson ,&nbsp;Jon Petur Joelsson ,&nbsp;Ari Jon Arason ,&nbsp;Arni Asbjarnarson ,&nbsp;Fridrik Runar Gardarsson ,&nbsp;Fredrik Lehmann ,&nbsp;Peter Teodorovic ,&nbsp;Saevar Ingthorsson ,&nbsp;Snaevar Sigurdsson ,&nbsp;Bryndis Valdimarsdottir ,&nbsp;Michael John Parnham ,&nbsp;Clive Page ,&nbsp;Jennifer Ann Kricker","doi":"10.1016/j.pupt.2025.102363","DOIUrl":"10.1016/j.pupt.2025.102363","url":null,"abstract":"<div><div>Epithelial barrier failure, a feature of several inflammatory lung diseases, contributes to exacerbations and disease progression. Acute exacerbations are often treated with macrolides, including azithromycin (AZM). In part, this is due to both primary antimicrobial and additional immunomodulatory actions, complemented by recently reported enhanced integrity of respiratory epithelial barriers. However, long-term “off label” use of macrolides is associated with increased bacterial resistance. We now introduce a new class of compounds, “Barriolides” that are analogues of AZM promoting airway epithelial barrier integrity <em>in vitro</em>, with negligible antibacterial activity. The lead compound is EP395 which does not affect cell viability up to 100 μM in VA10 bronchial epithelial cells. Treatment with EP395 for three weeks enhanced epithelial barrier integrity, measured by increased transepithelial electrical resistance, reduced paracellular flux in air-liquid interface culture and increased expression of tight junction proteins. EP395 also induced epidermal differentiation and formation of lamellar bodies, complemented by a relevant genetic footprint. In mice exposed to sulphur dioxide, pre-treatment with EP395 reduced extravasation of human serum albumin into the bronchoalveolar lavage fluid. These data demonstrate epithelial barrier-protecting effects of EP395, a promising candidate for treatment of chronic respiratory diseases without risk of bacterial resistance.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102363"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A disproportionality analysis of diabetes mellitus in patients treated with biologics for asthma and related conditions using FAERS data","authors":"Maria Gabriella Matera ,&nbsp;Luigino Calzetta ,&nbsp;Alfredo De Biase ,&nbsp;Davide Lauro ,&nbsp;Paola Rogliani ,&nbsp;Mario Cazzola","doi":"10.1016/j.pupt.2025.102377","DOIUrl":"10.1016/j.pupt.2025.102377","url":null,"abstract":"<div><h3>Background</h3><div>Biologics for asthma and related conditions target distinct immunologic pathways but may have differential effects on glucose metabolism. Emerging real-world evidence suggests a need to evaluate potential associations with diabetes mellitus (DM) and related metabolic adverse events (AEs).</div></div><div><h3>Objective</h3><div>To assess the disproportionality of DM and other metabolic AEs associated with six biologics approved for asthma and related conditions using data from the FDA Adverse Event Reporting System (FAERS).</div></div><div><h3>Methods</h3><div>Reported odds ratios (RORs) were calculated for metabolic events and DM for omalizumab, mepolizumab, benralizumab, reslizumab, dupilumab, and tezepelumab, comparing drug-specific AE profiles against the FAERS background.</div></div><div><h3>Results</h3><div>Omalizumab (ROR: 6.10) and benralizumab (ROR: 4.88) exhibited significant disproportionality regarding diabetes AEs, with mepolizumab also demonstrating an elevated ROR (2.80). For metabolic AEs, mepolizumab (ROR: 3.57) and omalizumab (ROR: 2.94) had the highest signals. Dupilumab showed the lowest RORs for both diabetes (0.10) and metabolic AEs (0.21).</div></div><div><h3>Conclusion</h3><div>This FAERS-based analysis identified a potential pharmacovigilance signal for DM associated with several biologics used to treat asthma and related conditions, most notably omalizumab and benralizumab. Similar patterns were observed for metabolic AEs, which reinforces the need for post-marketing studies and clinical awareness in patients with or at risk for metabolic disorders.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102377"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PM2.5 augments cigarette smoke-induced lung inflammation in mice by driving a stronger immune response: Potential beneficial effects of oleanolic acid","authors":"Jitender Chandel,&nbsp;Amarjit S. Naura","doi":"10.1016/j.pupt.2025.102379","DOIUrl":"10.1016/j.pupt.2025.102379","url":null,"abstract":"<div><div>Though cigarette smoke (CS) is primary risk factor for Chronic obstructive pulmonary disease (COPD), rising air pollution and higher concentrations of particulate matter (PM_2.5) in ambient air contribute substantially to COPD cases, particularly in smokers. However, the pathogenesis of COPD upon dual exposure to CS and PM_2.5 is not entirely known. Therefore, the impact of combined exposure to CS (9 cigarettes/day for 4 days) and PM_2.5 (single dose of 50 μg) on COPD pathogenesis was examined using mouse model in order to understand the key players behind the process. The data suggest that single exposure to PM_2.5 in CS pre-exposed mice triggered a strong inflammatory response, marked by switch from macrophage to neutrophilic inflammation, leading to severe deterioration in lung function compared to single hits. Furthermore, combined exposure led to robust increase in the levels of pro-inflammatory cytokines (G-CSF/KC/MCP-1/TNF-α/IL-1β/IL-6) in BALF as compared to the respective individual exposure. Interestingly, Oleanolic acid (OA) treatment protects against CS + PM_2.5-induced COPD-like pulmonary inflammation potentially by exerting antioxidant properties as reflected by data on BALF inflammatory cells, particularly neutrophils and various oxidative stress markers such as ROS/LPO/GSH/SOD/Catalase in lung tissue. Suppressed inflammation was associated with downregulation of gene expression of pro-inflammatory factors namely IL-1β, TNF-α, MIP-2 and normalization of proteinase-antiproteinase balance by downregulating gene expression of MMP-9 with simultaneous upregulation of its inhibitor TIMP-1. Reduced inflammatory response upon OA treatment correlates well with improved lung function. Overall, PM_2.5 exposure flares up the CS-induced lung inflammation linked to COPD, which is effectively ameliorated by OA.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102379"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the role of β2- and β3-adrenergic receptors in cystic fibrosis","authors":"Alessandro Cannavo ,&nbsp;Marika Comegna ,&nbsp;Alice Castaldo ,&nbsp;Caterina Vinciguerra ,&nbsp;Anna Lauritano ,&nbsp;Giulia Renata Franco ,&nbsp;Giovanna Casoria ,&nbsp;Graziamaria Corbi ,&nbsp;Giuseppe Rengo ,&nbsp;Giuseppe Castaldo","doi":"10.1016/j.pupt.2025.102385","DOIUrl":"10.1016/j.pupt.2025.102385","url":null,"abstract":"<div><div>Cystic fibrosis (CF) is an autosomal recessive disorder that affects multiple organs, with clinical manifestations, disease progression, and response to therapy varying among individuals. This effect is mainly caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel.</div><div>In recent decades, other genes and their allelic variants, beyond CFTR mutations, have been proposed as genetic modifiers of CF phenotype. For instance, different polymorphic β2-adrenergic receptor (β2AR) polymorphic variants have been reported in CF individuals and appear to influence correct receptor function. β2AR belongs to the βAR family, which includes three subtypes: β1AR, β2AR, and β3AR. These receptors are crucial G protein-coupled receptors (GPCRs) expressed in various cell types and serve as key modulators of cAMP production, making their function particularly relevant in CF pathophysiology. β2AR is abundantly expressed in airway epithelial and smooth muscle cells, and studies revealed that it plays a crucial role in modulating CFTR activity and smooth muscle contractility through cAMP signaling. For these reasons, β2-agonists are widely used in clinical healthcare to treat patients with obstructive airway disorders, including CF.</div><div>Emerging evidence has also supported a role for β3AR, which is expressed in the canine and human bronchial epithelium and have been reported to enhance ciliary motility and regulate CFTR function, making it a potential therapeutic target in CF.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102385"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional interplay between bradykinin receptors and transient receptor potential vanilloid-1 in lipopolysaccharide-induced acute lung injury in mice","authors":"Mayara Alves Amorim ,&nbsp;Vitor Hélio Souza Oliveira ,&nbsp;João B. Calixto ,&nbsp;Eunice André","doi":"10.1016/j.pupt.2025.102384","DOIUrl":"10.1016/j.pupt.2025.102384","url":null,"abstract":"<div><div>In this study, we investigated the functional interplay between bradykinin receptors and the transient receptor potential vanilloid-1 (TRPV1) channel in a mouse model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Lung and bronchoalveolar lavages were collected at 6 and 24 h after the induction of ALI and evaluated for changes in body weight, inflammatory marker levels, lung injury, and TRPV1 expression. Pretreatments with a TRPV1 antagonist (capsazepine) or B₁ and B₂ receptor antagonists, i.e., DALBK and HOE 140, respectively, were evaluated in this ALI mouse model. The histological score revealed higher levels of lung injury in mice treated with LPS (5 and 10 mg/kg), assessed at both 6 and 24 h, compared to the vehicle-treated group. A loss of body weight was observed within 24 h of ALI induction. Furthermore, collagen deposition, pulmonary oedema, leukocyte influx, and increased cytokine levels were also observed following LPS administration. Pretreatment with capsazepine, DALBK, or HOE 140 not only reversed all inflammatory parameters but also prevented the increased expression of TRPV1 observed in the lungs of mice subjected LPS-induced ALI. Our data suggest that, following LPS-induced ALI, bradykinin activates both B₁ and B₂ receptors associated with the subsequent activation of TRPV1. These findings suggest that bradykinin can activate both B₁ and B₂ receptors, which may contribute functionally to TRPV1 upregulation and activation during LPS-induced ALI. This novel pathway appears to sustain inflammation, offering a new therapeutic target for ALI and ARDS.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102384"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144830131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The era of multiple biologics: Is combination and switching an option in the management of severe asthma?","authors":"Emmanuel Oshiogwe Okwuofu ,&nbsp;Audrey Chee Hui Yong ,&nbsp;Jonathan Chee Woei Lim ,&nbsp;Johnson Stanslas","doi":"10.1016/j.pupt.2025.102375","DOIUrl":"10.1016/j.pupt.2025.102375","url":null,"abstract":"<div><h3>Background and objective</h3><div>The introduction of biologics therapies targeting specific cytokines relevant to asthma pathophysiology has changed the landscape in the treatment of severe asthma in both adults and children. However, the availability of multiple agents, inclusion criteria for randomised control trials (RCTs), variation in national and international guidelines, instances of treatment failures, and the potential of switching or combining biologic therapies, highlight the need for real-world evidence. Data from real-world studies of biologics in severe asthma may complement efficacy data obtained from RCTs and provide important post-marketing safety information. Additionally, these studies may help inform the design of future clinical trials, characterise the natural history of the disease, and support important translational research. This review highlights current evidence for the combination and switching of biologics in severe asthma and comorbid diseases that may serve as pointers for optimal clinical outcomes.</div></div><div><h3>Method</h3><div>Pubmed, Scopus, and Web of Science were searched using specified search strategies.</div></div><div><h3>Results</h3><div>Available evidence suggests that patients with severe asthma who received combination or switched biologics (omalizumab, benralizumab, reslizumab, mepolizumab, dupilumab, and Tezepelumab) in real-world settings experienced significant improvement in asthma control, exacerbation, and lung function. Although combining biologics is not currently a common practice, there are cases where biologic therapies were combined, discontinued, or switched.</div></div><div><h3>Conclusion</h3><div>Patients may benefit from the early and systematic consideration of combination and switching of biologic therapies in severe asthma.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102375"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigating systemic corticosteroid risks in COPD: A call for earlier triple therapy initiation","authors":"Luis J. Nannini","doi":"10.1016/j.pupt.2025.102360","DOIUrl":"10.1016/j.pupt.2025.102360","url":null,"abstract":"<div><div>Current GOLD guidelines recommend initial dual therapy with a LABA and LAMA for COPD patients with a high risk of exacerbations (at least two moderate or one severe exacerbation in the previous 12 months), with Inhaled Corticosteroids (ICS) added for specific phenotypes or continued exacerbations. Systemic corticosteroids (SCS) are advised for severe exacerbations, but cumulative SCS exposure is linked to significant adverse outcomes such as endocrine disorders and pneumonia. Studies suggest that after limited exacerbations, COPD patients may exhaust their “SCS credit,” increasing their risk of severe comorbidities. Earlier initiation of triple therapy in high-risk, symptomatic patients shows substantial benefits, including improved quality of life, compared to standard care. Like asthma management, SCS exposure in COPD should be minimised, and precision medicine should guide early triple therapy to preserve SCS use for future exacerbations.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102360"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Icaritin protects against airway inflammation by inhibiting the TLR4/NF-κB pathway in vivo and in vitro","authors":"Bo Xiao ,&nbsp;Guiming Zhou ,&nbsp;Lixia Hou ,&nbsp;Lihong Yang ,&nbsp;Zhimei Li ,&nbsp;Yuchun Cai ,&nbsp;Ailing Zhao ,&nbsp;Biwen Mo ,&nbsp;Dong Yao","doi":"10.1016/j.pupt.2025.102380","DOIUrl":"10.1016/j.pupt.2025.102380","url":null,"abstract":"<div><div>Icaritin, a bioactive phytomolecule derived from <em>Epimedium</em> flavonoids (EFs), has been shown to have anti-inflammatory, anti-proliferative, and pro-apoptotic properties. However, its potential mechanisms in asthma airway inflammation have not been elucidated. In this study, Ovalbumin (OVA)-induced asthma mouse model and human bronchial epithelial cells (BEAS-2B) were used to illustrate the effects and mechanisms of Icaritin on airway inflammation. Specific airway resistance (sRAW) was used to detect the airway hyperresponsiveness (AHR). Hematoxylin-eosin (H&amp;E) and periodic acid schiff (PAS) were used to detect the pathological changes. Bronchoalveolar lavage fluid (BALF) was used to detect the airway inflammatory cells. Serum and supernatants were used to detect the cytokines. Immunohistochemistry (IHC) and western blotting were used to detect the expression of TLR4, p-65, p-p65, IκBα, and p-IκBα. Cell Counting Kit-8 (CCK-8) was used to detect the cell viability. Icaritin suppressed AHR, attenuated eosinophilic infiltration and mucus hypersecretion, and significantly reduced the levels of OVA-specific cytokines in asthmatic mice. Moreover, Icaritin inhibited TLR4 expression, decreased phosphorylation of IκBα, and reduced NF-κB p65 activation in lung tissue of asthmatic mice. Further mechanistic studies showed that Icaritin reduces TLR4-induced inflammatory factor expression and blocks TLR4-activated NF-κB pathway in BEAS-2B cells. These findings demonstrate for the first time that Icaritin suppresses airway inflammation in asthma by inhibiting the TLR4/NF-κB pathway, suggesting its potential as a therapeutic agent for asthma.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102380"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted inhibition of IDO1 by Kushenol A enhances radiosensitivity in non-small cell lung cancer","authors":"Yingwei Zhu ,&nbsp;Yunqian Chu ,&nbsp;Hanjue Dai ,&nbsp;Enci Lu ,&nbsp;Qian Geng ,&nbsp;Qingying Xian ,&nbsp;Hua Jiang ,&nbsp;Wenyu Zhu","doi":"10.1016/j.pupt.2025.102362","DOIUrl":"10.1016/j.pupt.2025.102362","url":null,"abstract":"<div><div>Kushenol, a monomeric compound, was extracted from the roots of the medicinal plant Sophora flavescens. To explore the activity of Kushenol A in non-small cell lung cancer (NSCLC), CCK-8 assay, flow cytometry, and Western blot were performed. A xenograft mouse model was established. Our results demonstrated that Kushenol A treatment significantly enhanced the killing effect of radiation on NSCLC cells. Co-treatment with radiation and Kushenol A markedly reduced cell viability, increased intracellular ROS levels, and elevated the proportion of apoptotic cells compared to NSCLC cells treated with radiation alone. Animal experiments further confirmed that radiation therapy with simultaneous Kushenol A administration suppressed tumor growth and improved radiotherapy sensitivity compared to mice treated with radiation alone. Furthermore, Kushenol A did not produce significant toxic damage to the major organs of mice. Mechanistically, radiation therapy combined with Kushenol A treatment significantly upregulated protein levels of cleaved Caspase-3 and cleaved Caspase-9, leading to Bax translocation from the cytoplasm to mitochondria. Concurrently, Kushenol A treatment reduced NRF2 levels in the cytoplasm, thereby promoting an increase in ROS levels. Notably, Kushenol A enhanced tumor radiosensitivity by targeted inhibition of Indoleamine 2,3-dioxygenase 1 (IDO1). Taken together, our findings suggested that cotreatment with Kushenol A and radiation promoted the entry of Bax into mitochondria and activated the mitochondrial apoptotic pathway. Kushenol A exhibited targeted inhibition of IDO1, enhancing the sensitivity of non-small cell lung cancer to radiotherapy.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102362"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}