Journal of Molecular Medicine-Jmm最新文献

{"title":"Lipidomic insights on abdominal aortic aneurysm and peripheral arterial disease.","authors":"Helena Beatriz Ferreira, Fábio Trindade, Rita Nogueira-Ferreira, Adelino Leite-Moreira, Rita Ferreira, Marina Dias-Neto, M Rosário Domingues","doi":"10.1007/s00109-025-02524-1","DOIUrl":"https://doi.org/10.1007/s00109-025-02524-1","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) and peripheral arterial disease (PAD) are two cardiovascular diseases associated with considerable morbidity, mortality and quality of life impairment. As they are multifactorial diseases, several factors contribute to their pathogenesis, including oxidative stress and lipid peroxidation, and these may have key roles in the development of these pathologies. Alterations of the lipid metabolism and lipid profile have been reported in cardiovascular diseases but to a lesser extent in AAA and PAD. Modifications in the profile of some molecular lipid species, in particular, native phospholipid and triglyceride species were mainly reported for AAA, while alterations in the fatty acid profile were noticed in the case of PAD. Oxidized phospholipids were also reported for AAA. Although AAA and PAD have a common atherosclerotic root, lipidomics demonstrates the existence of distinct lipid. Lipidomic research regarding AAA and PAD is still scarce and should be set in motion to increase the knowledge on the lipid changes that occur in these diseases, contributing not only to the discovery of new biomarkers for diagnosis and prognosis assessment but also to tailor precision medicine in the clinical field.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517040","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":"Evaluation of circulating glypican 4 as a novel biomarker in disease - A comprehensive review.","authors":"A Muendlein, A Leiherer, H Drexel","doi":"10.1007/s00109-025-02520-5","DOIUrl":"https://doi.org/10.1007/s00109-025-02520-5","url":null,"abstract":"<p><p>Glypican 4 (GPC4), a member of the cell surface heparan sulfate proteoglycan family, plays a crucial role in regulating various cell signaling and developmental processes. Its ability to be released from the cell surface into the bloodstream through shedding makes it a promising blood-based biomarker in health and disease. In this context, circulating GPC4 has been initially proposed as an insulin-sensitizing adipokine being linked with various conditions of insulin resistance. In addition, serum levels of GPC4 can indicate glycocalyx shedding and associated pathophysiological states, such as systemic inflammation. Particularly in a morbid and elderly population, increased GPC4 concentrations may reflect general organ dysfunction and an advanced state of multimorbidity, showing a strong association with the prognosis of severe conditions such as heart failure or advanced cancer. This comprehensive review is the first to summarize the existing scientific knowledge on the role of circulating GPC4 as a novel diagnostic and prognostic biomarker across different pathologic conditions. We also discuss in detail the putative underlying pathophysiological mechanisms behind these findings.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442617","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":"Mesenchymal stem cell-derived extracellular vesicles in periodontal bone repair.","authors":"Mengbing Chen, Bo Huang, Xiaoxia Su","doi":"10.1007/s00109-025-02513-4","DOIUrl":"10.1007/s00109-025-02513-4","url":null,"abstract":"<p><p>Periodontitis is a chronic inflammatory disease that destroys tooth-supporting structures and poses significant public health challenges due to its high prevalence and links to systemic health conditions. Traditional treatments are effective in reducing the inflammatory response and improving the clinical symptoms of periodontitis. However, these methods are challenging to achieve an ideal treatment effect in alveolar bone repair. Mesenchymal stem cells (MSCs) represent a potential alternative for the treatment of periodontal bone defects due to their self-renewal and differentiation capabilities. Recent research indicates that MSCs exert their effects primarily through paracrine mechanisms. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) serve as pivotal mediators in intercellular communication, transferring microRNAs (miRNAs), messenger RNAs (mRNAs), proteins, and cytokines to recipient cells, thereby emulating the therapeutic effects of MSCs. In periodontitis, MSC-EVs play a pivotal role in immunomodulation and bone remodeling, thereby facilitating periodontal bone repair. As a cell-free therapy, MSC-EVs demonstrate considerable clinical potential due to their specialized membrane structure, minimal immunogenicity, low toxicity, high biocompatibility, and nanoscale size. This review indicates that MSC-EVs represent a promising approach for periodontitis treatment, with the potential to overcome the limitations of traditional therapies and offer a more effective solution for bone repair in periodontal disease. In this review, we introduce MSC-EVs, emphasizing their mechanisms and clinical applications in periodontal bone repair. It synthesizes recent advances, existing challenges, and future prospects to present up-to-date information and novel techniques for periodontal regeneration and to guide the improvement of MSC-EV therapy in clinical practice.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"137-156"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015334","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":"CircRNA CDR1AS promotes cardiac ischemia-reperfusion injury in mice by triggering cardiomyocyte autosis.","authors":"Lina Xuan, Jun Chen, Hua Yang, Junwei Hao, Siyun Li, Qingqing Zhang, Hailong Zhang, Shengjie Wang, Huishan Luo, Jianjun Guo, Xingmei Yang, Guangze Wang, Feihan Sun, Xiaolin Hu, Kai Kang, Lihua Sun","doi":"10.1007/s00109-024-02511-y","DOIUrl":"10.1007/s00109-024-02511-y","url":null,"abstract":"<p><p>Myocardial ischemia/reperfusion (IR) injury is a common adverse event in the clinical treatment of myocardial ischemic disease. Autosis is a form of cell death that occurs when autophagy is excessive in cells, and it has been associated with cardiac IR damage. This study aimed to investigate the regulatory mechanism of circRNA CDR1AS on autosis in cardiomyocytes under IR. The expression of CDR1AS increases after myocardial IR, and overexpression of CDR1AS detrimentally affects cardiac function, increases infarct area, promotes excessive autophagy, and blocks the flow of autophagy to induce autosis after IR. Conversely, knockdown of CDR1AS reversed the autophagy-related markers caused by IR, increasing cardiomyocyte activity, improving cardiac dysfunction and infarct area, and restoring the flow of autophagy. Further analysis of RNA sequencing and validation experiments revealed that CDR1AS aggravated autophagic damage, increased autophagosome accumulation, and promoted autosis by inhibiting the levels of LAMP2 and mTORC1 proteins. Additionally, RIP and pull-down assays showed that CDR1AS interacts with LAMP2 or mTORC1. First-time evidence reveals that circRNA CDR1AS regulates lysosomal membrane proteins by regulating the mTORC1/ULK1 pathway during myocardial IR-induced autosis. This suggests that maintaining moderate autophagy is a crucial part of the fight against myocardial IR damage. KEY MESSAGES: CDR1AS expression was significantly increased in myocardium following IR. CDR1AS can increase the occurrence of autosis after IR. CDR1AS reduces the phosphorylation of ULK1, promoting the formation of autophagosomes. CDR1AS binds to LAMP2 and blocks the autophagosome clearance pathway. The specific mechanism of CDR1AS regulating IR is achieved by regulating autosis.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"219-237"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928329","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":"Rare variants in cardiomyopathy genes predispose to cardiac injury in severe COVID-19 patients of African or Hispanic ancestry.","authors":"Hui-Qi Qu, Matthew S Delfiner, Chethan Gangireddy, Anjali Vaidya, Kenny Nguyen, Isaac R Whitman, JuFang Wang, Jianliang Song, Michael R Bristow, Charles F McTiernan, Glenn S Gerhard, Hakon Hakonarson, Arthur M Feldman","doi":"10.1007/s00109-024-02510-z","DOIUrl":"10.1007/s00109-024-02510-z","url":null,"abstract":"<p><p>In one of the earliest reports from China during COVID-19, it was noted that over 20% of patients hospitalized with the disease had significant elevations of troponin, a marker of myocardial tissue damage, that put them at a higher risk. In a hypothesis-independent whole exome sequencing (WES) study in hospitalized COVID-19 patients of diverse ancestry, we observed putative enrichment in pathogenic variants in genes known to be involved in the pathogenesis of cardiomyopathy. This observation led us to hypothesize that the observed high morbidity and mortality in these patients might be due to the presence of rare genetic factors that had previously been silent but became relevant as a consequence of the severe stress inflicted by an infection with SARS-CoV-2. To test this hypothesis, we analyzed our WES data generated from a cohort of 325 patients sequentially admitted for COVID-19 infection. In this predominantly minority population (53.9% African ancestry and 37.9% Hispanic/Latin ancestry), our initial analysis screen identified 263 variants that were identified as highly deleterious (HD) from a total of 26,661 variants of interest that represented 215 genes. Of those, we identified 46 genes (in 58 patients) harboring rare HD coding variants that were previously implicated in dilated cardiomyopathy and were considered as disease initiators for the severe COVID-19 in this study. These findings offer valuable insights into the molecular mechanisms and genetic susceptibility to heart injury in severe COVID-19. KEY MESSAGES: COVID-19 may cause cardiac damage in some affected patients without a plausible biological explanation. Our study reveals an enrichment of highly deleterious variants linked to cardiomyopathy in severe COVID-19 patients. Genetic profiling unveils the molecular basis of severe COVID-19-related heart injury, potentially aiding in patient stratification.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"175-185"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering metabolic shifts in Gaucher disease type 1: a multi-omics study.","authors":"Franklin Ducatez, Marc G Berger, Carine Pilon, Thomas Plichet, Céline Lesueur, Juliette Berger, Nadia Belmatoug, Stéphane Marret, Soumeya Bekri, Abdellah Tebani","doi":"10.1007/s00109-024-02512-x","DOIUrl":"10.1007/s00109-024-02512-x","url":null,"abstract":"<p><p>Gaucher disease (GD), an autosomal recessive lysosomal disorder, primarily affects the lysosomal enzyme β-glucocerebrosidase (GCase), leading to glucosylceramide accumulation in lysosomes. GD presents a wide spectrum of clinical manifestations. This study deploys immune-based proteomics and mass spectrometry-based metabolomics technologies to comprehensively investigate the biochemical landscape in 43 deeply phenotyped type 1 GD patients compared to 59 controls. Conventional and systems biology approaches have been used to analyze the data. The results show promising biological imprints. Elevated phosphatidylcholines in GD patients suggest altered lipid metabolism, potentially due to their increased synthesis. This points to endoplasmic reticulum stress and impaired lipid trafficking, commonly seen in lysosomal diseases. GD patients exhibit an inflammatory profile with elevated cytokines and autoimmune-like inflammation, even in treated patients, highlighting the complexity of GD-related immune imbalances. Mitochondrial dysfunction clues are found through increased oxidative stress markers and altered acylcarnitine profiles in GD patients, suggesting mitochondrial membrane dysfunction affecting carnitine-carrying capacity. Furthermore, platelet count, splenectomy, treatment, and clinical traits were associated with specific omics features, providing insights into GD's clinical heterogeneity and potential diagnostic markers. Autophagy inhibition appears pivotal in GD, driving lipid synthesis, impaired mitochondrial function, and inflammation through chronic activation of mTORC1. Despite limitations like focusing on type 1 GD and using targeted omics approaches, this study provides valuable insights into GD metabolic and immune dysregulation. It lays the basis for future comprehensive investigations into GD manifestations with broader scope and molecular coverage. KEY MESSAGES: The study sheds light on metabolic and immune dysregulation in Gaucher disease. Gaucher disease patients showed elevated phosphatidylcholines, disrupted lipid metabolism, and inflammation profiles. Signs of mitochondrial dysfunction are evident in Gaucher disease patients, with autophagy inhibition significantly affecting lipid synthesis, mitochondrial function, and inflammation via chronic activation of mTORC1.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"187-203"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911123","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":"VSMC-specific TRPC1 deletion attenuates angiotensin II-induced hypertension and cardiovascular remodeling.","authors":"Xin Wen, Yuefeng Peng, Wenqing Yang, Yuzhong Zhu, Fan Yu, Li Geng, Xianfeng Wang, Xiaoyan Wang, Xiaodong Zhang, Yi Tang, Lei Feng, Tingting Zhou, Hongliang Jia, Liu Yang","doi":"10.1007/s00109-024-02509-6","DOIUrl":"10.1007/s00109-024-02509-6","url":null,"abstract":"<p><p>Transient receptor potential canonical 1 (TRPC1) channel, a Ca²⁺-permeable ion channel widely expressed in vasculature, has been reported to be involved in various cardiovascular disorders. However, the pathophysiological function of vascular smooth muscle cell (VSMC)-derived TRPC1 in hypertension and hypertensive cardiovascular remodeling remains to be defined. In this study, we found increased TRPC1 expression in both angiotensin II (AngII)-treated VSMCs and aortas from AngII-infused mice. VSMC-specific TRPC1 deficiency strikingly attenuated AngII-induced vasoconstriction, hypertension, vascular remodeling, and cardiac hypertrophy. Mechanistically, AngII activated enhancer of zeste homolog 2 (EZH2) to stimulate TRPC1 expression, induced calcium influx and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK), which in turn triggered VSMC proliferation and migration and exacerbated hypertension and cardiovascular remodeling. Treatment with EZH2 inhibitor reduced VSMC proliferation and migration and alleviated vasoconstriction and hypertension in AngII-infused mice. Together, we revealed the pathogenic role of the EZH2-TRPC1-MEK/ERK pathway in AngII-induced hypertension and cardiovascular damage. TRPC1 or EZH2 inhibition may represent a desirable therapeutic target for the treatment of hypertension. KEY MESSAGES: AngII activates AT1R-EZH2-TRPC1 pathway in VSMCs and aortas of hypertensive mice. TRPC1 promotes VSMC proliferation and migration via MEK/ERK signaling. Inhibition of TRPC1 or EZH2 alleviates hypertension and cardiovascular remodeling.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"205-218"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916253","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 lncRNA in the differentiation of adipose-derived stem cells: from functions to mechanism.","authors":"Yujing Wang, Yuxi Zhou, Kun Li","doi":"10.1007/s00109-024-02507-8","DOIUrl":"10.1007/s00109-024-02507-8","url":null,"abstract":"<p><p>Adipose-derived stem cells (ADSCs) have become one of the best seed cells widely studied and concerned in tissue engineering because of their rich sources and excellent multi-directional differentiation ability, which are expected to play a practical application role in tissue defect, osteoporosis, plastic surgery, and other fields. However, the differentiation direction of ADSCs is regulated by complex factors. Long non-coding RNAs (lncRNAs) are RNA molecules longer than 500 nucleotides that do not encode proteins and can act as signaling RNAs in response to intracellular and extracellular stimuli. Recently, accumulating evidence has revealed that lncRNAs could regulate the cell cycle and differentiation direction of ADSCs through various mechanisms, including histone modification, binding to RNA-binding proteins, and regulating the expression of miRNAs. Therefore, enriching and elucidating its mechanism of action as well as targeting lncRNAs to regulate ADSCs differentiation have potential prospects in tissue regeneration applications such as bone, blood vessels, and adipose. In this review, we summarize the role and mechanism of lncRNAs and its complexes in the multi-directional differentiation of ADSCs and discuss some potential approaches that can exert therapeutic effects on tissue defects by modulating the expression level of lncRNAs in ADSCs. Our work might provide some new research directions for the clinical applications of tissue engineering.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"125-135"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873415","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":"Drosophila modeling to identify causative genes and reveal the underlying molecular mechanisms for primary ovarian insufficiency.","authors":"Yanbin Ma, Yuxin Liu, Man Xu, Xinhuan Yin, Chenyu Hu, Xiaohang Yang, Wanzhong Ge","doi":"10.1007/s00109-025-02516-1","DOIUrl":"10.1007/s00109-025-02516-1","url":null,"abstract":"<p><p>Primary ovarian insufficiency (POI) is a disease defined as a reduction in ovarian function under the age of 40 and represents the main cause of female infertility. In recent years, many genetic mutations associated with POI have been identified using high-throughput sequencing technology. However, one big challenge today is to determine the disease-causing gene associations through functional assessment. Here, we develop a Drosophila model to study the POI-associated genes and provide in vivo functional evidence to validate the POI-causing genes. We use two different Gal4 drivers, in combination with RNAi transgene, and systematically knockdown 51 genes associated with POI. We show that 22 and 17 genes are required for female fertility and ovarian development in somatic and germline cells, respectively. Moreover, we also focus on AlaRS-m, the Drosophila ortholog of the human AARS2 gene, for further functional characterization. Depletion of AlaRS-m in ovarian somatic cells leads to decreased female fertility and a reduction in ovary size, as well as egg chamber degeneration. We also provide evidence that AlaRS-m deficiency causes mitochondrial dysfunction, overproduction of ROS, and apoptotic cell death. Our findings demonstrate that Drosophila can be used as a platform to assess the functional significance of POI-associated genes identified in genomic studies and illustrate the molecular mechanism underlying the pathogenesis of POI. KEY MESSAGES: • One hundred fourteen genes associated with POI are identified, and 76 of them have Drosophila orthologs. • Twenty-two genes and 17 genes are required for female fertility when knocked down in the Drosophila ovarian somatic cells and germline cells, respectively. • AlaRS-m/AARS2 deficiency causes female fertility defects with egg chamber degeneration.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"239-253"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034694","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":"Indole-3-Aldehyde alleviates lung inflammation in COPD through activating Aryl Hydrocarbon Receptor to inhibit HDACs/NF-κB/NLRP3 signaling pathways.","authors":"Pengtao Wang, Wei Tao, Qiujie Li, Wanting Ma, Wei Jia, Yuting Kang","doi":"10.1007/s00109-024-02506-9","DOIUrl":"10.1007/s00109-024-02506-9","url":null,"abstract":"<p><p>Indole-3-aldehyde (I3A) is an intestinal microbial metabolite that regulates inflammation in various inflammatory diseases; however, its role in chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to investigate the anti-inflammatory effects and molecular mechanisms of I3A in COPD. We constructed in vivo models using cigarette smoke (CS)-stimulated mice and in vitro models using cigarette smoke extract (CSE)-stimulated MH-S cells. The results demonstrated that I3A significantly alleviated bronchial obstruction in mice with COPD and reduced the expression of inflammatory factors such as TNF-α, IL-1β, and IL-6. Additionally, I3A decreased the levels of matrix metalloproteinases MMP2, MMP12, and inhibited the NF-κB p65/NLRP3 pathways. Further investigation revealed that I3A inhibited NF-κB activity by suppressing p65 phosphorylation and nuclear translocation in CSE-stimulated MH-S cells. The activation of the NF-κB and NLRP3 signaling pathways is mediated by histone deacetylase 5 (HDAC5) and HDAC6, both of which are inhibited by I3A. Subsequent experiments indicated that aryl hydrocarbon receptor (AHR) knockdown attenuated the inhibitory effect of I3A on pro-inflammatory cytokines and the HDACs/NF-κB/NLRP3 signaling pathways, highlighting the dependence of I3A's anti-inflammatory effects on the AHR receptor. KEY MESSAGES: I3A effectively reduced lung inflammation in COPD mice by inhibiting the NF-κB pathway. In CSE-stimulated MH-S cells, I3A suppressed p65 phosphorylation and nuclear translocation, thereby inhibiting NF-κB activity. The activation of the NF-κB/NLRP3 pathways by HDAC5 and HDAC6 was diminished by I3A. Through the activation of the AHR receptor, I3A suppressed the activities of HDAC5/6, leading to a decrease in inflammatory factor levels.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"157-174"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}