European journal of pharmacology最新文献

{"title":"Decoding aortic dissection from potential drug targets to genetic risk factors: A Mendelian randomization study","authors":"Jiaqi Hou ,&nbsp;Lihua Lin ,&nbsp;Jing Huang,&nbsp;Qianqian Chai,&nbsp;Shujuan Wang,&nbsp;Xiang Liu,&nbsp;Qian Liu","doi":"10.1016/j.ejphar.2025.177838","DOIUrl":"10.1016/j.ejphar.2025.177838","url":null,"abstract":"<div><h3>Aims</h3><div>The aortic dissection (AD) is defined as the destruction of the tunica media and separation of the aortic wall, which can be fatal. To date, there is no clinical medication that has been developed to effectively prevent the progression of AD. Therefore, it is imperative to identify risk factors associated with AD and to discover potential therapeutic targets.</div></div><div><h3>Methods</h3><div>To identify therapeutic targets for AD, we used cis-expression quantitative trait loci (cis-eQTL) data from the eQTLgen Consortium and genome-wide association analysis (GWAS) data from the Finngen Consortium for Mendelian randomization (MR). Colocalization analysis screened drug targets with shared SNPs in the disease. Drug prediction and molecular docking verified the targets' medicinal value. Finally, mediation analysis was performed to explore how drug targets might influence AD development.</div></div><div><h3>Results</h3><div>Using MR, we identified 76 genes exhibiting significant associations. Subsequent colocalization analysis revealed five drug targets sharing genetic signals with AD. Drug prediction analyses were conducted, and molecular docking demonstrated a robust association between the predicted drugs and the implicated genes. Furthermore, our findings suggest that diastolic blood pressure, hip circumference and ascending aorta diameter may serve as potential mediating factors in the development of AD.</div></div><div><h3>Conclusion</h3><div>This study identified five potential pharmacological targets for AD. Additionally, drug prediction and molecular docking were employed to assess the therapeutic potential of these targets. The findings of this research are anticipated to offer valuable screening indicators for AD prediction and facilitate advancements in AD drug development.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1002 ","pages":"Article 177838"},"PeriodicalIF":4.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293486","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":"SPHK2 inhibition alleviates chronic intermittent hypoxia-induced inflammation in adipose tissue by decreasing endoplasmic reticulum stress","authors":"Longyi Ran ,&nbsp;Chang Wei ,&nbsp;Xinyu Wang ,&nbsp;Yuean Zhao ,&nbsp;Peijun Li ,&nbsp;Dong Huang ,&nbsp;Wenyu Gu ,&nbsp;Xu Wu ,&nbsp;Zongan Liang ,&nbsp;Xinyuan Wang ,&nbsp;Linjing Gong","doi":"10.1016/j.ejphar.2025.177841","DOIUrl":"10.1016/j.ejphar.2025.177841","url":null,"abstract":"<div><div>Obstructive Sleep Apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent disorder that significantly elevates the risk of cardiovascular and metabolic complications. Lipid metabolism disturbances, a common comorbidity in OSA, are closely associated with CIH-induced adipose tissue inflammation, yet the underlying mechanisms remain poorly defined. In this study, we established a CIH mouse model to investigate the roles of Sphingosine Kinase 2 (SPHK2) and endoplasmic reticulum stress (ERS) in CIH-induced lipid metabolic disturbances. Mice were exposed to normal air (NA) or CIH for 4 or 12 weeks. Serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were measured to assess systemic lipid metabolism. CIH group significantly elevated SPHK2 expression and activated the PERK-ATF4-CHOP signaling pathway in epididymal (eWAT) and subcutaneous white adipose tissue (scWAT), leading to increased NLRP3 inflammasome accumulation, oxidative stress, and adipocyte apoptosis. Administration of the SPHK2 inhibitor ABC294640, opaganib, attenuated these effects, reducing ERS activation and restoring lipid homeostasis. Further, treatment with the ERS inhibitor 4-BPA suppressed oxidative stress and inflammatory cytokines, alleviating CIH-induced adipose tissue inflammation. In contrast, ERS activation by thapsigargin reversed the protective effects of SPHK2 inhibition, exacerbating metabolic and inflammatory dysregulation. In summary, our findings highlight the critical role of SPHK2 and ERS in CIH-induced adipose tissue inflammation and lipid metabolic disturbances. Pharmacological inhibition of SPHK2 represents a promising therapeutic approach for mitigating OSA-related lipid metabolic disturbances.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1002 ","pages":"Article 177841"},"PeriodicalIF":4.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293554","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":"Reduced NF-κB/NLRP3/IL-18 signaling increases the protective effect of L-glutamine against LPS-induced retinal inflammation in mice: Utilization of network pharmacology and experimental validation.","authors":"Manar Mohammed El Tabaa, Maram Mohammed El Tabaa, Mohamed Mohsen, Hamdi Mohamed Abo-Alazm, Donia Mohamed Abd Elaziz, Mariam Akram, Eman Mohamed Eldeeb, Zeina Ahmed Nadar, Omar Mamoun Fahmy, Mark Ashraf Mansy, Mina Bahig Fakhory, Ahmed S Doghish, Mahmoud A Elrebehy, Mohammed Salah Elballal, Lobna A Saleh, Osama A Mohammed","doi":"10.1016/j.ejphar.2025.177840","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177840","url":null,"abstract":"<p><p>Regarding retinal inflammation, NF-κB activation has been demonstrated to stimulate the NLRP3 inflammasome, which subsequently promotes IL-18 production, resulting in heightened inflammatory damage. Concurrently, GLP-1 has shown a role in reducing the likelihood of retinal inflammation. Nonetheless, the exact mechanism by which GLP-1 can reduce inflammation in the retina by modulating NF-κB/NLRP3/IL-18 axis remains unknown. Therefore, it may be worthwhile investigating the effects of L-glutamine (L-glu), a GLP-1 inducer, on LPS-induced retinal inflammation in rats, considering the involvement of NF-κB/NLRP3/IL-18 signaling. This study utilized the strategy of network pharmacology with subsequent experimental validation to predict the targets and associated pathways related to L-glu and retinal inflammation. To authenticate the in vivo pharmacological efficacy of L-glu, 60 mice were divided into 4 groups. The expression and level of GLP-1, in addition to IGF-2 and IL-18 levels were assayed. Gene expression of PPARγ and XO, as well as protein expression of p-TLR4, SIRT1, NLRP3, and caspase-1 were determined. The Nrf2/HO-1, MDA, and TAC were also detected. Retinal histopathology and immunostaining were lastly done. Network analysis identified 251 overlapping targets and 462 pathways between L-glu and retinal inflammation. Experimentally, L-glu enhanced the IGF-2-dependent PPARγ expression by boosting GLP-1 secretion. PPARγ then restricted TLR4 phosphorylation and XO expression to activate SIRT1/Nrf2 and alleviate oxidative stress. SIRT1 simultaneously inhibited the NF-κB-driven secretion of TNF-α and IL-6, as well as the ensuing activation of NLRP3/caspase-1/IL-18. These findings suggested that L-glu may confer protection against LPS-induced retinal inflammation in a GLP-1-dependent manner via prohibiting NF-κB/NLRP3/IL-18 pathway.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177840"},"PeriodicalIF":4.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293553","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":"Therapeutic effects of finerenone and exenatide on diabetes-induced heart failure: A combined approach targeting inflammation and oxidative stress","authors":"Ayşe Koçak ,&nbsp;Emirhan Günek ,&nbsp;Elif Aydın ,&nbsp;Meliha Koldemir Gündüz ,&nbsp;Güllü Kaymak","doi":"10.1016/j.ejphar.2025.177826","DOIUrl":"10.1016/j.ejphar.2025.177826","url":null,"abstract":"<div><div>Cardiovascular complications, particularly diabetic cardiomyopathy and heart failure, are leading causes of morbidity and mortality in patients with diabetes mellitus. This study aimed to investigate the therapeutic potential of finerenone and exenatide, individually and in combination, in mitigating diabetes-induced cardiac injury. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, exhibits strong anti-fibrotic and anti-inflammatory properties in cardiovascular and renal diseases. Exenatide, a glucagon-like peptide-1 receptor agonist, is recognized for its glucose-lowering effects and additional cardioprotective actions, including antioxidant and anti-inflammatory activities. The combination of these agents was hypothesized to exert synergistic effects by targeting complementary pathological pathways involved in diabetic cardiomyopathy progression.</div><div>Type 1 diabetes was induced in rats by a single high-dose streptozotocin injection. Animals were divided into five groups: control, STZ, STZ with finerenone, STZ with exenatide, and STZ with both finerenone and exenatide. Cardiac tissues and serum samples were analyzed for oxidative stress markers (TOS, TAS), inflammatory cytokines (IL-6, IL-1β, TNF-α), and myocardial injury biomarkers (cTnT, cTnI) through RT-qPCR and Western blotting. NRF2 pathway activation was also evaluated to assess antioxidant responses.</div><div>STZ-induced diabetic rats showed significant increases in hyperglycemia, inflammation, oxidative stress, and myocardial injury. Treatment with either finerenone or exenatide alone improved several parameters; however, the combination therapy provided the most substantial cardioprotective effects, with marked reductions in oxidative stress and inflammation and enhanced NRF2 expression.</div><div>These findings suggest that the combined administration of finerenone and exenatide offers superior protection against diabetes-induced cardiac injury compared to monotherapies, supporting a dual-targeted therapeutic approach for diabetic cardiomyopathy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1002 ","pages":"Article 177826"},"PeriodicalIF":4.2,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265694","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":"p38 protein as a therapeutic target for sepsis-induced organ dysfunction","authors":"Shan Miao ,&nbsp;Rui Zhang ,&nbsp;Guiping Guo ,&nbsp;Xinshang Wang ,&nbsp;Bin Zhang ,&nbsp;Long Li ,&nbsp;Jin Wang ,&nbsp;Yan Weng ,&nbsp;Xiaopeng Shi ,&nbsp;Shanbo Ma ,&nbsp;Chenxi Lu","doi":"10.1016/j.ejphar.2025.177833","DOIUrl":"10.1016/j.ejphar.2025.177833","url":null,"abstract":"<div><div>Sepsis is a systemic disorder with a dysregulated host response caused by infection and is associated with multiple organ dysfunction and a high risk of mortality. Several factors are involved in the complex pathophysiological process of sepsis, including the inflammatory response, immune response, mitochondrial dysfunction, and coagulation cascade. p38 proteins, a class of mitogen-activated protein kinases, play key roles in inflammatory/immune responses and are involved in essential cellular processes. Previous studies have shown that p38 is highly expressed in sepsis and sepsis-induced organ damage and is involved in complex biological, signaling-driven processes. Therefore, this review aims to summarize the efficacy and mechanism of action of p38 in treating sepsis and sepsis-induced multiple-organ damage. First, the basic structure, signal transduction mechanism of p38, and its role in the pathological process of sepsis are comprehensively described. Second, the mechanism of p38 in sepsis-induced multiple-organ damage (including the heart, liver, lung, and brain) is described. Finally, the discovery and application of p38 inhibitors and the role of p38 in sepsis is discussed. This review provides a new therapeutic target for sepsis-induced multiple-organ dysfunction.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1002 ","pages":"Article 177833"},"PeriodicalIF":4.2,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263406","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":"Drug-related visual blurring: findings from the U.S. Food and Drug Administration Adverse Event Reporting System database","authors":"Shi-Nan Wu ,&nbsp;Xiao-Dong Chen ,&nbsp;Qian-Ting Liu ,&nbsp;Lin Chen ,&nbsp;Le Sun ,&nbsp;Wen-Ying Guan ,&nbsp;Jia-Yu Kang ,&nbsp;Caihong Huang ,&nbsp;Jiaoyue Hu ,&nbsp;Zuguo Liu","doi":"10.1016/j.ejphar.2025.177820","DOIUrl":"10.1016/j.ejphar.2025.177820","url":null,"abstract":"<div><h3>Background</h3><div>Visual blurring is one of the most common symptoms in ophthalmology, and one of the important causes of secondary visual blurring is drug-related. This study assesses the risk of drug-related visual blurring using a large real-world database.</div></div><div><h3>Methods</h3><div>We analyzed adverse event reports from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database between January 2004 and September 2024. Disproportionality analysis algorithm were used. Drugs related with positive signals for visual blurring were categorized, and the risk levels, number of reports, and drug-induced onset times were quantified.</div></div><div><h3>Results</h3><div>Disproportionality analysis of the FAERS database identified 119 drugs with positive signals for visual blurring, primarily in the following categories: ophthalmic medications (Lifitegrast, Reporting Odds Ratio [ROR] = 53.24; 95 % Confidence Interval [CI]: 49.19–57.61), endocrine medications (Semaglutide, ROR = 3.26 [2.84–3.75]), nervous system medications (Pregabalin, ROR = 4.15 [3.93–4.37]), oncology medications (Encorafenib, ROR = 5.38 [4.37–6.62]), antimuscarinic medications (Fesoterodine, ROR = 6.77 [5.08–9.03]), and other medications (Dupilumab, ROR = 8.39 [8.16–8.64]). The top three drugs associated with the highest incidence of blurred vision as an adverse event are lifitegrast, oxymetazoline, and olopatadine. Antimuscarinic Medications had the shortest drug-induced onset time. Women (63.87 %) and middle-aged to elderly individuals [Age (mean ± standard deviation): 53.59 ± 18.79] were the main populations affected by drug-related visual blurring.</div></div><div><h3>Conclusion</h3><div>Preventing drug-related vision issues is vital. Early risk assessment and intervention with personalized medication can reduce side effects, ensure safety, and improve quality of life.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1002 ","pages":"Article 177820"},"PeriodicalIF":4.2,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257700","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":"Comparative evaluation of human gammaglobulin and methylprednisolone versus Naja atra antivenom in preventing venom-induced ulceration: A cellular and murine model study","authors":"Wangang Qin ,&nbsp;Youhai Yu ,&nbsp;Lirong Ding ,&nbsp;Hongtian Zhou ,&nbsp;Huiwen Yu ,&nbsp;Mimi Lay ,&nbsp;Zhanpeng Zhuo ,&nbsp;Hao Wen ,&nbsp;Yangyu Ou ,&nbsp;Junting Huang ,&nbsp;Min Jiang ,&nbsp;Zhanzheng Yang ,&nbsp;Suhua Kuang ,&nbsp;Fei Long ,&nbsp;Zijing Liang ,&nbsp;Qing Liang","doi":"10.1016/j.ejphar.2025.177821","DOIUrl":"10.1016/j.ejphar.2025.177821","url":null,"abstract":"<div><div>Cytotoxins (CTXs) from <em>Naja atra</em> (<em>N. atra</em>) venom induce tissue ulceration, and the efficacy of Chinese <em>N. atra</em> antivenom in preventing venom-induced ulceration is limited. In this study, we purified CTXs from <em>N. atra</em> venom and assessed the preventive effects of human gammaglobulin (HGG) and methylprednisolone (MPS) on ulceration provoked by <em>N. atra</em> venom and CTXs, with Chinese <em>N. atra</em> antivenom as the standard treatment. At the cellular level, within 6 h of exposure, antivenom (5 μl/ml), HGG (100 μg/ml), and low-dose MPS (0.2 μg/ml) significantly improved the survival rate (74 %, 71 %, 73 %) of L6 cells exposed to <em>N. atra</em> venom (2 μg/ml). High-dose MPS (500 μg/ml) showed no protective effect. In mice, antivenom (100 μl/ml), HGG (10 mg/ml), and MPS (400 μg/ml) reduced mortality (0 %, 40 %, and 80 %) and ulcer incidence (0 %, 0 %, 40 %) and area (0 mm², 0 mm², 6.48 mm²). Interestingly, delayed HGG administration post-exposure showed superior L6 cell survival rates (82 % vs 55 %) and reduced ulcer incidence (20 % vs 40 %) and area (1.582 mm² vs 8.916 mm²) compared with antivenom. Notably, the combination of antivenom and MPS resulted in lower survival rates (67 % vs 74 %) in L6 cells and a higher incidence (60 % vs 0 %) of ulcers, with larger ulcer areas (3.359 mm² vs 0 mm²) compared to those of antivenom alone. In conclusion, HGG demonstrates non-inferior preventive effects against snakebite ulcers compared to antivenom, while MPS, particularly in low doses (0.2 μg/ml), offers limited protection. The combination of antivenom and MPS is not recommended.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1002 ","pages":"Article 177821"},"PeriodicalIF":4.2,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254063","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":"Molsidomine ameliorates DEXA-induced insulin resistance: Involvement of HMGB1/JAK1/STAT3 signaling pathway","authors":"Howida M. Abdelaziz,&nbsp;Marwa E. Abdelmageed,&nbsp;Ghada M. Suddek","doi":"10.1016/j.ejphar.2025.177832","DOIUrl":"10.1016/j.ejphar.2025.177832","url":null,"abstract":"<div><div>Insulin resistance (IR) is a serious clinical syndrome that establishes the basis for illnesses like type 2 diabetes (T2D). In this study, the effectiveness of molsidomine (MOLS) which is a nitric oxide (NO) doner, on dexamethasone (DEXA)- induced IR in rats was examined. Male <em>Wistar</em> rats were managed with MOLS (5 and 10 mg/kg) orally once daily for 7 days before DEXA injection (1 mg/kg, intraperitoneally (i.p.)) and 7 days concurrent with DEXA injection. The findings showed that MOLS reduced low-density lipoprotein cholesterol (LDL-C), fasting serum glucose and insulin, homeostatic model assessment of insulin resistance (HOMA-IR), alanine transaminase (ALT), aspartate transaminase (AST), oral glucose tolerance test (OGTT), and triglycerides (TGs). These findings revealed that MOLS was successful in reducing DEXA-induced IR. Moreover, MOLS was associated with a large increase in reduced glutathione (GSH) and superoxide dismutase (SOD) activity as well as a significant decrease in the levels of malondialdehyde (MDA) in hepatic and aortic tissues. When compared to rats treated with DEXA, MOLS significantly decreased the levels of pro-inflammatory cytokine interlukin-6 (IL-6), high mobility group box 1 (HMGB1), phosphorylated Janus kinase1/phosphorylated signal transducer and activator of transcription 3 (p-JAK1/p-STAT3), and nuclear factor kappa-B-p65 subunit (NF-κB-p65) in hepatic tissues. Additionally, MOLS reduced inflammation and necrosis and increased B cell/lymphoma 2 (BCL-2) and lowered caspase-3 levels and attenuated liver histopathological changes. Moreover, aortic expression levels of NF-κB-p65 and IL-6 were reduced upon MOLS treatment. All these findings show that MOLS protects rats from DEXA-induced IR by inhibiting HMGB1/JAK1/STAT3 signaling, regulating oxidative stress and inflammatory pathways, and having an antioxidant and anti-inflammatory effect.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1002 ","pages":"Article 177832"},"PeriodicalIF":4.2,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144255058","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":"Celebrating 1000 Issues of EJP: A Journey of Pharmacological Science","authors":"","doi":"10.1016/S0014-2999(25)00559-X","DOIUrl":"10.1016/S0014-2999(25)00559-X","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1001 ","pages":"Article 177805"},"PeriodicalIF":4.2,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144229484","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":"lncRNA CASC9 stabilizes MUC1 by binding to U2AF2 to inhibit cellular ferroptosis and alleviate LPS-induced cell injury","authors":"Keke Chen ,&nbsp;Chengjie Chen ,&nbsp;Sihu Chen ,&nbsp;Xiang Zheng ,&nbsp;Guoquan Pan ,&nbsp;Yafeng Liang","doi":"10.1016/j.ejphar.2025.177818","DOIUrl":"10.1016/j.ejphar.2025.177818","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis-induced acute lung injury (ALI) is a critical condition with a limited number of treatment options. The regulatory role of long noncoding RNA cancer susceptibility candidate 9 (lncRNA CASC9) in ferroptosis, a specific type of cell death, has been linked to this condition.</div></div><div><h3>Methods</h3><div>In this study, HPAEpiCs were treated with lipopolysaccharide (LPS) to model sepsis-induced acute lung injury. Various assays were employed, including RNA immunoprecipitation (RIP) and RNA pull-down to investigate lncRNA CASC9 interactions with U2 small nuclear RNA auxiliary factor 2 (U2AF2) and Mucin 1 (MUC1), Cell Counting Kit-8 (CCK-8) for cell viability, ELISA for inflammatory cytokines, Calcein-AM/PI staining for live/dead cell visualization, Reagent kit detection of lipid reactive oxygen species (ROS) and Malondialdehyde (MDA) assays for oxidative stress markers, iron and Glutathione (GSH) assays for redox status, qPCR for gene expression, and Western blot for protein levels.</div></div><div><h3>Results</h3><div>The expression of lncRNA CASC9 was significantly decreased in LPS-induced cell models. Overexpression of lncRNA CASC9 reduced ferroptosis, as indicated by improved cell viability, decreased inflammatory cytokines, and restored redox homeostasis (reduced MDA and ROS, and iron levels, and increased GSH level). The lncRNA CASC9 interacts with U2AF2 to stabilize MUC1 mRNA, enhance MUC1 expression and reduce ferroptosis. Knockdown of U2AF2 reversed these effects, highlighting lncRNA CASC9's regulatory role in ferroptosis via MUC1 stabilization. MUC1 overexpression similarly reduced LPS-induced ferroptosis, supporting the protective role of the lncRNA CASC9/U2AF2/MUC1 pathway.</div></div><div><h3>Conclusion</h3><div>This study demonstrated that lncRNA CASC9 regulates sepsis-induced ALI by stabilizing MUC1 mRNA through U2AF2 interaction, thereby inhibiting ferroptosis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1002 ","pages":"Article 177818"},"PeriodicalIF":4.2,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254062","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}