Toxicology and applied pharmacology最新文献

{"title":"Evaluating N-acetylcysteine for mitigating cisplatin-induced oxidative stress and ionocyte damage in a zebrafish model","authors":"Szu-Jung Chen ,&nbsp;Ciao-Ling Wu ,&nbsp;Li-Yih Lin ,&nbsp;Jiun-Lin Horng","doi":"10.1016/j.taap.2025.117401","DOIUrl":"10.1016/j.taap.2025.117401","url":null,"abstract":"<div><div>In this study, we examined the protective effects of <em>N</em>-acetylcysteine (NAC) against cisplatin-induced toxicity in zebrafish embryos. Cisplatin (<em>cis</em>-diamminedichloroplatinum II), a widely used anticancer drug, is associated with significant cytotoxic effects toward non-target tissues, including renal and ototoxic damage. Using zebrafish embryos exposed to cisplatin, we evaluated survival rates, hatching rates, ionocyte densities, oxidative stress, and platinum accumulation. NAC co-treatment significantly enhanced survival and hatching rates, preserved ionocyte density, mitigated oxidative stress, and reduced platinum accumulation. These findings highlight ionocytes as an effective model for assessing non-renal toxicity due to their high metabolic activity and mitochondrial abundance. The results suggest that NAC might serve as a co-therapeutic agent to alleviate cisplatin-induced toxicity during chemotherapy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"501 ","pages":"Article 117401"},"PeriodicalIF":3.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120927","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":"Integrated transcriptomics and metabolomics unravel the key metabolic pathways involved in the therapeutic mechanism of Salvianic acid A against hepatic fibrosis","authors":"Yunan Zhang ,&nbsp;Yan Zhang ,&nbsp;Jianan Zhang ,&nbsp;Wenfang Lai ,&nbsp;Guiqing He ,&nbsp;Jichan Shi ,&nbsp;Chuan Zhang ,&nbsp;Liyan Xiong ,&nbsp;Tingfang Wang ,&nbsp;Fei Ye ,&nbsp;Xiangao Jiang","doi":"10.1016/j.taap.2025.117398","DOIUrl":"10.1016/j.taap.2025.117398","url":null,"abstract":"<div><div>Effective drugs for the clinical treatment of hepatic fibrosis have not yet been identified. Salvianic acid A (SAA) protective mechanisms primarily include anti-inflammation, anti-oxidative stress, and modulation of immune system function. Metabolic dysfunction is well recognized as the driver for hepatic fibrosis. However, the precise action mode and underlying mechanism of SAA in modulating hepatic metabolism to combat hepatic fibrosis remain incompletely understood. This study aimed to investigate the metabolic mechanism by which SAA improves hepatic fibrosis based on metabolomics and transcriptomics profiling. A mouse model of carbon tetrachloride (CCl₄)-induced hepatic fibrosis mouse model was established, and protective effects of SAA were evaluated through pathological characteristics. Integrated metabolomics and transcriptomics analysis revealed three key altered metabolic pathways: bile secretion, carbohydrate digestion and absorption, and regulation of lipolysis in adipocytes. SAA modulated the bile secretion pathway, dependent on reducing water channel protein <em>Aqp1</em>, cholesterol synthesis enzyme <em>Hmgcr</em> and Na⁺/K⁺-ATPase enzyme <em>Atp1a3</em>, accompanied by up-regulating metabolites glutathione and glucose levels. SAA also regulated carbohydrate digestion and absorption by decreasing the glucose homeostasis-related <em>Akt3</em>, essential enzyme <em>G6pc</em> for gluconeogenesis/glycogenolysis and glucose transporter <em>Atp1a3</em> with a concomitant increase of metabolites D-galactose, maltose, and sucrose levels. Moreover, SAA improved lipolysis in adipocytes in liver fibrosis through inhibiting lipolysis related <em>Prkg1,</em> lipid transporter <em>Fabp4,</em> lipolysis-associated <em>Akt3</em> and increasing lipolysis mediator <em>Adrb3</em>, along with upregulated levels of metabolites adenosine monophosphate and norepinephrine. In conclusion, SAA alleviates hepatic fibrosis through modulating metabolic disorders, mainly relying on the metabolic improvements of bile secretion, carbohydrate digestion and absorption and adipocyte lipolysis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117398"},"PeriodicalIF":3.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102666","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":"Fluvoxamine, an inhibitor of CYP1A2, improves CS-induced pulmonary inflammation through estrogen deficiency","authors":"Siyu-Yang ,&nbsp;Ruibing-Sun ,&nbsp;Liqing-Wang ,&nbsp;Mingzhe-Cao","doi":"10.1016/j.taap.2025.117395","DOIUrl":"10.1016/j.taap.2025.117395","url":null,"abstract":"<div><div>Chronic obstructive pulmonary disease (COPD), one of the most prevalent respiratory diseases worldwide, exhibits marked gender disparities, with women disproportionately affected. Current therapeutic modalities for COPD are relatively ineffective as the available drugs cannot considerably delay disease progression or substantially affect inflammation. Therefore, the suppression of inflammatory responses is considered an essential management strategy for COPD. Fluvoxamine, a CYP1A2 inhibitor with anti-inflammatory effects, and CYP1A2 affects estrogen metabolism. However, its potential as a COPD treatment and interaction with estrogen in women are unclear. This study explored fluvoxamine's efficacy in female mice with cigarette smoke (CS)-induced COPD. Administering 8 mg/kg fluvoxamine intraperitoneally markedly reduced CS-induced lung damage, lowering histopathological injury and pro-inflammatory cytokines in bronchoalveolar lavage fluid and serum. RNA-seq analysis revealed that fluvoxamine significantly suppressed the upregulation of inflammation-related genes. Furthermore, the KEGG and GSEA analysis of differentially expressed genes in lung transcriptomics revealed that the metabolism of xenobiotics by cytochrome P450 and JAK-STAT signaling pathway were regulated after fluvoxamine treatment. WB and ELISA assay also demonstrated a significant decrease in CYP1A2 and estrogen levels following treatment with fluvoxamine or tamoxifen. Crucially, fluvoxamine matched tamoxifen (an estrogen inhibitor) in improving lung structural parameters (mean linear intercept, destructive index). These results suggest fluvoxamine mitigates COPD by inhibiting CYP1A2, reducing inflammatory mediators and estrogen. The proposed mechanism combines estrogen metabolism modulation and anti-inflammatory action, offering dual therapeutic benefits. This study positions fluvoxamine as a novel COPD treatment candidate, particularly for women, targeting hormonal and inflammatory pathways. Further research is needed to validate clinical translation.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"501 ","pages":"Article 117395"},"PeriodicalIF":3.3,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094876","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":"Lung microbiota metabolite L-malic acid attenuates the airway inflammation in asthma by inhibiting ferroptosis","authors":"Lishan Lin ,&nbsp;Danhui Huang ,&nbsp;Haohua Huang ,&nbsp;Lingyan Xie ,&nbsp;Yi Huang ,&nbsp;Cuiping Ye ,&nbsp;Lanhe Chu ,&nbsp;Yujie Qiao ,&nbsp;Xiaojing Meng ,&nbsp;Shaoxi Cai ,&nbsp;Hangming Dong","doi":"10.1016/j.taap.2025.117396","DOIUrl":"10.1016/j.taap.2025.117396","url":null,"abstract":"<div><div>Inhaled environmental allergens, such as house dust mites (HDM), have been shown to induce an inflammatory reaction, tissue injury, and increased airway sensitivity in the lungs, ultimately leading to the development of allergic asthma. The imbalance of respiratory microbiota and metabolites plays a crucial role in the progression of allergic asthma. However, there is limited knowledge available regarding the alterations in respiratory microbiota and metabolites and their impact on the host in the context of asthma. The aim of this study was to investigate the potential pathways involved in the development of asthma through the analysis of lung flora and metabolites. A mouse model of house dust mite (HDM)-induced asthma was established, and alveolar lavage samples were collected for microbiome 16S rRNA sequencing and untargeted metabolic analysis. Microbiological analyses indicated a significant alteration in the microbiota after 4 and 6 weeks of HDM nebulisation stimulation. This was characterized by a decrease in microbial diversity, as well as reductions in the relative proportion of <em>Gallionella</em> and <em>Lactobacillus</em>. Conversely, the abundance of <em>Flavobacterium</em> and <em>Ralstonia</em> increased in the HDM4W and HDM6W groups, respectively. Metabolomic analyses revealed seven distinct metabolites, among them L-malic acid, which were linked to signaling pathways in a mouse model of HDM-induced asthma. The correlation analysis demonstrated a positive association between L-malic acid and <em>Rhodanobacter</em> and <em>Nocardioides</em>. L-malic acid was discovered to be efficacious in reducing airway inflammation in mice with house dust mite-induced asthma. Further analysis revealed that this change was linked to lipid peroxidation and changes in ferroptosis markers, namely GPX4 and FTH. These findings suggest that L-malate inhibits ferroptosis. However, the introduction of ferroptosis inducers, such as Erastin, was observed to negate the beneficial effect of butyrate. In summary, this research implies that the respiratory microbiota metabolite L-malic acid lessens airway inflammation in asthma by inhibiting ferroptosis, offering a potential approach for managing asthma.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117396"},"PeriodicalIF":3.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089733","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":"Corrigendum to “FOXO3a reactivation mediates the synergistic cytotoxic effects of rapamycin and cisplatin in oral squamous cell carcinoma cells” [Toxicology and Applied Pharmacology 251 (2011) 8–15]","authors":"Liang Fang ,&nbsp;Huiming Wang ,&nbsp;Lin Zhou ,&nbsp;Da Yu","doi":"10.1016/j.taap.2025.117397","DOIUrl":"10.1016/j.taap.2025.117397","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"501 ","pages":"Article 117397"},"PeriodicalIF":3.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085737","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":"Chronic arsenic exposure of ovarian surface and fallopian tube cultures induces giant and/or multinucleated cells with phagocytosis-like properties and an inflammatory phenotype","authors":"Cristina M. Andrade-Feraud ,&nbsp;Arlet M. Acanda de la Rocha ,&nbsp;Noah E. Berlow ,&nbsp;Santiago Duque ,&nbsp;Alexander Velazco ,&nbsp;Diego Castillo ,&nbsp;Baylee Holcomb ,&nbsp;Ebony R. Coats ,&nbsp;Yasmin R. Ghurani ,&nbsp;Catherine M. Lucey ,&nbsp;Brandon Pearson ,&nbsp;Tomás R. Guilarte ,&nbsp;Diana J. Azzam","doi":"10.1016/j.taap.2025.117394","DOIUrl":"10.1016/j.taap.2025.117394","url":null,"abstract":"<div><div>Chronic exposure to arsenic, a toxic metalloid frequently found in groundwater and food, represents a significant environmental health risk and has been implicated in the etiology of several cancers, including ovarian cancer. However, the precise pathways through which arsenic exerts its toxic impact on the ovary are not fully understood. This study investigates the impact of chronic arsenic exposure at environmentally relevant concentrations (75 ppb or μg/L) on primary human ovarian surface (OCE1) and fallopian tube (FNE1) cultures derived from the same donor. These heterogeneous cultures provide a unique, human-relevant platform to investigate how chronic arsenic exposure influences distinct cell types within a shared microenvironment. Prolonged arsenic exposure induced significant cytotoxicity and promoted the formation of giant and/or multinucleated cells in both cultures. These cells exhibited phagocytosis-like properties, actively engulfing apoptotic debris. Transcriptomic analyses and pathway enrichment revealed robust activation of pro-inflammatory signaling, notably the canonical NF-κB pathway. This was marked by nuclear translocation of the NF-κB p65 subunit and elevated expression and secretion of pro-inflammatory cytokines, including TNFα, IL-6, and IL-8, driving a sustained inflammatory response. Moreover, arsenic-exposed cells displayed persistent DNA damage, as indicated by increased γ-H2AX foci, accompanied by nuclear structural alterations and elevated expression of cancer stem cell markers, including OCT2, CD133, and ALDH1. These findings suggest that arsenic-induced inflammation and genomic instability converge to promote a tumor-supportive microenvironment, highlighting the potential role of chronic arsenic exposure in ovarian carcinogenesis, particularly in the context of inflammation-driven carcinogenesis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117394"},"PeriodicalIF":3.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071873","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":"Screening of oxidative stress components of cigarette smoke based on machine learning model integration","authors":"Yuxin Hong ,&nbsp;Jiayu Lv ,&nbsp;Yuxuan Hong ,&nbsp;Jiahao Wang ,&nbsp;Xuhao Huang ,&nbsp;Chao Chen","doi":"10.1016/j.taap.2025.117387","DOIUrl":"10.1016/j.taap.2025.117387","url":null,"abstract":"<div><div>Cigarette smoke, a complex mixture of more than 7000 chemicals, poses a significant threat to human health, with oxidative stress being an important mechanism in its associated diseases. Traditional methods for assessing the toxicity of cigarette smoke components, such as animal and cell-based assays, are often limited by their high cost and time consumption. This study integrates multiple machine learning algorithms and diverse data sources to construct a robust predictive model for identifying oxidative stress-inducing components in cigarette smoke. Utilizing a multi-dataset, multi-target and multi-algorithm modeling strategy, we developed an integrated model comprising 704 sub-models. These models were trained from 9 datasets related to reactive oxygen species (ROS)-associated pathways. The integrated model demonstrated better performance in external validation compared to individual models, predicting 974 ROS-positive components from 7111 cigarette smoke components. These components were clustered into 10 major classes, providing new insights into the structural diversity of oxidative stress-inducing components in cigarette smoke. Our findings offer a novel approach for enhancing the predictive capability of toxicity models and advancing the understanding of oxidative stress-related toxicity in cigarette smoke components.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117387"},"PeriodicalIF":3.3,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942420","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 role of tungsten in modulating DNA double-strand break repair and class switch recombination","authors":"Rowa Bakadlag ,&nbsp;Hsiang Chou ,&nbsp;Cynthia Guilbert ,&nbsp;Vincent M. Luo ,&nbsp;Alexandre Orthwein ,&nbsp;Koren K. Mann","doi":"10.1016/j.taap.2025.117392","DOIUrl":"10.1016/j.taap.2025.117392","url":null,"abstract":"<div><div>Tungsten, a transition metal with widespread applications, is increasingly recognized as an environmental contaminant with potential health impacts. While tungsten exposure has been previously associated with increased DNA damage, its specific effects on DNA repair mechanisms remain poorly understood. Here, we found that tungsten alone did not induce DNA damage <em>in vitro</em>, as assessed by γ-H2AX phosphorylation. However, tungsten exacerbated DNA double-strand breaks induced by genotoxic agents, delayed γ-H2AX resolution, and induced cell cycle arrest. Mechanistically, GFP-based reporter assays revealed that tungsten impairs both homologous recombination (HR) and non-homologous end joining (NHEJ), which coincided with reduced recruitment of critical repair proteins, including BRCA1, 53BP1, and ATM at DSB sites. To assess functional consequences of impaired DNA repair due to tungsten exposure, we examined immunoglobulin (Ig) class switch recombination (CSR), a critical antibody diversification process reliant on the repair of DSBs. Using the CH12F3 B cell line, we showed that tungsten significantly impaired cytokine stimulated-CSR from IgM to IgA without affecting cell proliferation or activation-induced cytidine deaminase (<em>Aicda</em>) expression. Furthermore, <em>ex vivo</em> activation of splenic B cells confirmed that tungsten exposure inhibits CSR from IgM to IgG1, independent of cell proliferation. Together, these data indicate that tungsten exposure impairs canonical DSB repair pathways and CSR, highlighting the potential consequences for immune function upon environmental or occupational exposure to tungsten.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117392"},"PeriodicalIF":3.3,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027970","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":"Integration of computational models to predict botanical phytochemical constituent clearance routes by the Extended Clearance Classification System (ECCS)","authors":"Yitong Liu ,&nbsp;Michael Lawless ,&nbsp;Amy L. Roe ,&nbsp;Stephen S. Ferguson","doi":"10.1016/j.taap.2025.117385","DOIUrl":"10.1016/j.taap.2025.117385","url":null,"abstract":"<div><div>The Extended Clearance Classification System (ECCS) is a framework that predicts a chemical's predominant rate-determining clearance route: metabolism, hepatic uptake, or renal clearance. The ECCS prediction is based upon molecular weight, ionization state, and membrane permeability, which could be predicted by quantitative structure-activity relationship (QSAR) models. The ECCS also indicates potential chemical interactions via drug-metabolizing enzymes and transporters. This study used the ECCS to evaluate phytochemical constituents and predicted drug-metabolizing enzyme and transporter pathways to understand botanical clearance in humans. First, 82 phytochemical constituents were classified into six ECCS classes based on QSAR-predicted properties. Next, constituents in classes 1A and 2 were further explored as potential substrates for 18 drug-metabolizing enzymes followed by predictions for hepatic clearance, while constituents in classes 3 and 4 leveraged predictions for glomerular filtration and renal transporters. Finally, potential interactions between phytochemical constituents and drugs were discussed. Results showed that more than half of the phytochemical constituents were in ECCS class 2, whose Phase I metabolism were predicted to be predominantly mediated by CYP3A4, CYP2D6, and CYP1A2. Additionally, over 20 % of the phytochemical constituents fell into ECCS class 4, which were predicted to be predominantly cleared in unchanged forms by glomerular filtration and active renal secretion by OAT1/3 or OCT2. Classes 1A and 2 compounds exhibit high interaction potential via CYPs, while classes 3 and 4 compounds have relatively low potential for renal uptake transporter mediated interactions. This study represents a data-driven framework for exploring and contextualizing botanical constituent information to inform safety evaluations.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117385"},"PeriodicalIF":3.3,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049976","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":"Harnessing FDA-approved dipyridamole to inhibit NLRP3 inflammasome and improve outcomes of acute lung injury in sepsis","authors":"Xiuhui Chen ,&nbsp;Yutong Zheng ,&nbsp;Xiaofeng Zhang ,&nbsp;Anran Zheng ,&nbsp;Junjun Huang ,&nbsp;Guoliang Deng ,&nbsp;Xuna Wu ,&nbsp;Yuying Peng ,&nbsp;Xiaoling Zhang ,&nbsp;Renshan Chen ,&nbsp;Qing Xiao ,&nbsp;Weijun Ye","doi":"10.1016/j.taap.2025.117383","DOIUrl":"10.1016/j.taap.2025.117383","url":null,"abstract":"<div><div>Aberrant activation of the NLRP3 inflammasome is critically involved in sepsis-induced acute lung injury (ALI), with inhibition of this pathway emerging as a promising therapeutic approach. This study identifies Dipyridamole, an FDA-approved drug, as a novel inhibitor of the NLRP3 inflammasome. Mechanistically, Dipyridamole suppresses mitochondrial ROS release and directly interacts with NEK7, thereby preventing its association with NLRP3 and impeding inflammasome complex assembly. In an LPS-induced sepsis model, Dipyridamole significantly ameliorated ALI, reduced inflammatory responses, and improved survival rates in model mice. Additionally, Dipyridamole effectively inhibited NLRP3 inflammasome activation in lung tissue. These findings position Dipyridamole as a potent NLRP3 inflammasome inhibitor with substantial therapeutic potential for managing sepsis-induced ALI.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117383"},"PeriodicalIF":3.3,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936899","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}