Frontiers in Molecular Neuroscience最新文献

{"title":"Decoding pain chronification: mechanisms of the acute-to-chronic transition.","authors":"Shunwei Zhang, Youzhi Ning, Yiyi Yang, Guo Mu, Yongkui Yang, Changhe Ren, Changli Liao, Cehua Ou, Yue Zhang","doi":"10.3389/fnmol.2025.1596367","DOIUrl":"10.3389/fnmol.2025.1596367","url":null,"abstract":"<p><p>Pain chronification is a multidimensional and active pathophysiological process, not merely a consequence of prolonged nociception. This review proposes a four-domain mechanistic framework to elucidate the transition from acute to chronic pain. At the molecular-cellular level, persistent neuroinflammation-driven by activated glial cells and pro-inflammatory mediators such as TNF-α and IL-1β-leads to peripheral and central sensitization through enhanced excitability and ion channel dysregulation. In parallel, epigenetic mechanisms such as DNA methylation and histone modifications alter the expression of pain-related genes (e.g., SCN9A, BDNF), establishing a long-term transcriptional predisposition to chronic pain. These changes converge on maladaptive neural plasticity, characterized by aberrant synaptic strengthening, cortical map reorganization, and disrupted functional connectivity, which embed pain into persistent network states. Moreover, psychosocial factors-including catastrophizing, affective distress, and impaired top-down regulation-amplify pain through feedback loops involving the prefrontal cortex, amygdala, and hypothalamic-pituitary-adrenal (HPA) axis. By integrating these four interconnected domains, we highlight critical windows for mechanism-informed, temporally targeted interventions that may interrupt pain chronification and enable a shift toward proactive, personalized pain prevention.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1596367"},"PeriodicalIF":3.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608196","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":"Research hotspots and emerging trends in MicroRNA therapy for neuropathic pain: a bibliometric analysis (2009-2024).","authors":"Yiqiang Zhang, Shushu Chen, Jiangtao Chi, Qinghua Gao, Yujie Li, Huaizhao Wang, Yuanyuan Yu","doi":"10.3389/fnmol.2025.1610844","DOIUrl":"10.3389/fnmol.2025.1610844","url":null,"abstract":"<p><strong>Objective: </strong>This study systematically investigates the evolving trends, research hotspots, and future directions in microRNA-based therapy for neuropathic pain (NP) through bibliometric analysis.</p><p><strong>Methods: </strong>We extracted literature related to microRNA interventions in NP from the Web of Science Core Collection database, spanning January 2009 to December 2024. A comprehensive analysis was conducted on publication trends, authorship patterns, institutional collaborations, national contributions, journal preferences, co-citation networks, and keyword clusters.</p><p><strong>Results: </strong>The final analysis included 250 articles, showing a steady increase in publications over the past 15 years. China was the most productive country, while the United States demonstrated the highest scientific influence. The top three institutions by publication count were Xuzhou Medical University, Nanjing Medical University, and the Chinese Academy of Medical Sciences and Peking Union Medical College. <i>Pain</i> was identified as the most co-cited journal. Keyword analysis revealed \"differential expression\" with the strongest citation burst intensity, while \"peripheral nerve injury,\" \"mechanical allodynia,\" and \"proliferation\" emerged as recent high-frequency terms.</p><p><strong>Conclusion: </strong>In the field of microRNA therapy for neuropathic pain, investigations into peripheral nerve injury mechanisms, neuroinflammation regulation, and miRNA differential expression patterns have been identified as current research hotspots. Emerging frontiers are now shifting toward three strategic directions: (1) development of targeted delivery systems, (2) precision modulation of nociceptive circuits, and (3) individualized therapeutic strategies. Collectively, miRNAs demonstrate significant potential as innovative NP treatments. While clinical translation of miRNA-based therapies remains a critical research priority, key challenges persist in optimizing target specificity (particularly sequence homology discrimination among miRNA isoforms) and ensuring biocompatibility of delivery platforms.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1610844"},"PeriodicalIF":3.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608198","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":"Critical gene network and signaling pathway analysis of the extracellular signal-regulated kinase (ERK) pathway in ischemic stroke.","authors":"Rui Mao, Lei Wang, Haitao Zhang, Jiaojiao Gong, Hua Liu","doi":"10.3389/fnmol.2025.1604670","DOIUrl":"10.3389/fnmol.2025.1604670","url":null,"abstract":"<p><strong>Background and objective: </strong>Ischemic stroke remains a leading cause of morbidity worldwide, demanding reliable biomarkers and mechanistic insights to inform personalized diagnostic and therapeutic strategies. We sought to integrate multiple ischemic stroke transcriptomic datasets, identify key extracellular signal-regulated kinase (ERK) pathway-related biomarkers, delineate immune-stromal heterogeneity, and develop a nomogram for clinical risk assessment.</p><p><strong>Methods: </strong>We retrieved three public microarray datasets (GSE22255, GSE16561, GSE58294) and merged two of them (GSE22255, GSE16561) into a discovery cohort after stringent batch correction. Differential expression analyses were performed using the limma package in R, followed by weighted gene co-expression network analysis (WGCNA) to identify ERK-associated gene modules. Gene Ontology (GO) enrichment and protein-protein interaction (PPI) network analyses further elucidated the functional and interaction landscapes of the key ERK pathway genes, collectively termed GSERK. Subsequently, hub genes were prioritized using cytoHubba, and their diagnostic utility was validated by receiver operating characteristic (ROC) analyses in both discovery and validation cohorts. Four machine learning algorithms (Boruta, SVM, LASSO, random forest) corroborated hub gene robustness. Finally, we stratified ischemic stroke samples by immune-stromal profiling and constructed a GSERK-based nomogram to predict stroke risk.</p><p><strong>Results: </strong>A total of 140 differentially expressed genes (DEGs) were identified, with the ERK-related subset (GSERK) highlighted for its pivotal roles in ischemic stroke pathogenesis. Five hub GSERK genes (GADD45A, DUSP1, IL1B, JUN, and GADD45B) emerged from cytoHubba. DUSP1, GADD45A, and GADD45B showed robust diagnostic accuracy (AUC: 0.75-0.91), confirmed across discovery and validation sets. Immune-stromal clustering revealed two distinct stroke subgroups with hyperinflammatory or quiescent stromal phenotypes. A GSERK-based nomogram demonstrated a strong bootstrap-validated C-index, underscoring its potential for clinical risk stratification.</p><p><strong>Conclusion: </strong>These findings affirm the significance of ERK signaling in ischemic stroke, unveil critical GSERK biomarkers with promising diagnostic and therapeutic implications, and present a novel GSERK-based nomogram for precision risk assessment. Further studies, including experimental validation and multi-center clinical trials, are warranted to refine this integrative approach toward personalized stroke care.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1604670"},"PeriodicalIF":3.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600182","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":"How endothelial cell metabolism shapes blood-brain barrier integrity in neurodegeneration.","authors":"Jiaxin Wang, Yuchun Chen, Shiteng Chen, Zihan Mu, Jun Chen","doi":"10.3389/fnmol.2025.1623321","DOIUrl":"10.3389/fnmol.2025.1623321","url":null,"abstract":"<p><strong>Background/objective: </strong>Endothelial cells, a monolayer of cells adjacent to blood vessels, play a critical role in maintaining vascular function through metabolic pathways such as glycolysis, fatty acid, and amino acid metabolism. Recent studies have revealed their significant involvement in neurodegenerative diseases, although the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>By reviewing literature from the past decade, we summarized the metabolic alterations and functional changes of endothelial cells in neurological disorders.</p><p><strong>Results: </strong>In neurodegenerative diseases such as stroke, Alzheimer's disease, multiple sclerosis, and aging, metabolic dysregulation in cerebral vascular endothelial cells disrupts their normal function and is closely associated with blood-brain barrier impairment.</p><p><strong>Conclusion: </strong>Aberrant endothelial cell metabolism compromises the integrity of the blood-brain barrier and exacerbates the pathological progression of neurodegenerative diseases. Our review further explores the therapeutic potential of targeting endothelial cell metabolism in various pathological contexts, aiming to provide novel insights for the prevention and treatment of related disorders.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1623321"},"PeriodicalIF":3.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600183","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":"Whole-genome sequencing shows modulation of neurodegenerative genes by <i>Withania somnifera</i> in human SK-N-SH cells.","authors":"Eshita Sharma, Dilip Mehta, Nikita Jadhav, Gunjan Gujrati, S Dhananya, Manju Moorthy, Gopalakrishna Ramaswamy, Yundong Zhou, Sujit Nair","doi":"10.3389/fnmol.2025.1512727","DOIUrl":"10.3389/fnmol.2025.1512727","url":null,"abstract":"<p><strong>Background: </strong>Aging is driven by several primary and secondary hallmarks that manifest with age, of which neurodegenerative diseases are important manifestations. The ability to decelerate or reverse aging, and promote healthy aging, has garnered great interest in recent times. In traditional medicine, <i>Withania somnifera</i> (WS) or Ashwagandha has been recognized for its adaptogenic and rejuvenative effects.</p><p><strong>Methods: </strong>To investigate WS-modulated global gene expression profiles, we performed whole-genome sequencing of WS-treated human neuroblastoma SK-N-SH cells at different doses (50 and 100 μg/mL) and time points (3 h and 9 h) and validation by quantitative real-time PCR (qRT-PCR) and immunoblotting. Disease enrichment analysis for brain-related disorders was performed by DisGeNET.</p><p><strong>Results: </strong>Using differential gene expression analyses, we identified 19,945 WS-modulated genes. Of these, 2,403 and 177 genes were significantly (<i>p</i> ≤ 0.05) upregulated and downregulated, respectively, by WS treatment. Interestingly, different patterns of gene expression were exhibited in dose-dependent (9 upregulated, 1 downregulated, 100 μg/mL 3 h vs. 50 μg/mL 3 h; 21 upregulated, 86 downregulated, 100 μg/mL 9 h vs. 50 μg/mL 9 h) and temporal kinetics (210 upregulated, 6 downregulated, 50 μg/mL 9 h vs. 50 μg/mL 3 h; 8 upregulated, 49 downregulated, 100 μg/mL 9 h vs. 100 μg/mL 3 h). Furthermore, qRT-PCR experiments validated the RNA-seq results. WS-modulated genes were implicated in Alzheimer's disease, migraine, Parkinson's disease, bipolar disorder, cognition, stress, anxiety, forgetfulness, sleep disorders, and substance abuse among others.</p><p><strong>Conclusion: </strong>Taken together, our transcriptomic profiling study revealed for the first time that WS may modulate key genes in neurodegenerative disorders with potential beneficial implications for brain-related disorders and healthy aging.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1512727"},"PeriodicalIF":3.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600184","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":"Exploring research trends and hotspots in PI3K/Akt signaling pathway in ischemic stroke: a bibliometric analysis.","authors":"Yingquan Liu, Yu Ye, Lin Bai, Fan Dai, Xingxing Su, Peijia Hu, Hongliang Cheng","doi":"10.3389/fnmol.2025.1613702","DOIUrl":"10.3389/fnmol.2025.1613702","url":null,"abstract":"<p><strong>Objective: </strong>This study explores potential therapeutic strategies by determining the current research status, hotspots, and development trends through bibliometric analysis of the PI3K/Akt in ischemic stroke (IS).</p><p><strong>Methods: </strong>We searched the Web of Science Core Collection for publications on IS and the PI3K/Akt pathway, covering January 1, 2010, to December 31, 2024. VOSviewer and CiteSpace software were used to analyze research hotspots and cutting-edge topics in the field and generate visual maps of relevant countries, institutions, authors, journals, keywords, and references.</p><p><strong>Results: </strong>A total of 635 publications were analyzed. The number of publications indicates a steady annual increase in research output. China, Capital Medical University, and Wang Lei were identified as the most prolific country, institution, and author, respectively. The top three contributing journals were <i>Brain Research</i>, <i>Journal of Ethnopharmacology</i>, and <i>Frontiers in Pharmacology</i>. Autophagy, microglia and neuroinflammation, bioinformatics approaches, and traditional Chinese medicine (TCM) are not only current research areas but also important trends for future research. Notably, targeting IS with TCM holds significant potential for translating basic research findings into clinical applications.</p><p><strong>Conclusion: </strong>This bibliometric analysis provides an in-depth overview of research on the PI3K/Akt pathway in IS, revealing current research status, hotspots, and future research trends. This will provide valuable guidance and direction for developing novel therapeutic strategies targeting this pathway.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1613702"},"PeriodicalIF":3.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12230055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583721","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":"Peroxisome dynamics and inter-organelle interactions in neuronal health and disease.","authors":"Ruth E Carmichael","doi":"10.3389/fnmol.2025.1603632","DOIUrl":"10.3389/fnmol.2025.1603632","url":null,"abstract":"<p><p>Peroxisomes are essential organelles, present in all nucleated cells, with key roles in lipid and redox homeostasis. They are important for maintaining healthy cell function, with defects in peroxisome biogenesis and/or metabolism leading to disease. Notably, patients with peroxisomal diseases exhibit predominantly neurological phenotypes, and peroxisomes are observed to be altered in a range of neurodegenerative conditions, highlighting the crucial roles they play in the brain. While most studies so far have focused on the contribution of peroxisomal metabolism, it is becoming apparent that many different aspects of peroxisome biology are necessary for healthy neural function. Peroxisomes are highly dynamic, responding to cellular needs with changes in number, shape and distribution. Furthermore, they do not act in isolation but instead interact and cooperate with a range of organelles to carry out their roles. This review summarizes our current knowledge on the importance of peroxisome dynamics and inter-organelle interactions in neuronal function and dysfunction. It considers their impact on neuronal physiology, and discusses the evidence that defects in these processes are associated with neurological pathophysiology and may thus represent a novel therapeutic target for treating diseases affecting the nervous system. Finally, the review outlines the current knowledge gaps relating to the mechanisms by which peroxisome dynamics and inter-organelle interactions influence neuronal (dys)function, proposing potential new research directions to address these and further our understanding of the multi-faceted roles peroxisomes play in brain health and disease.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1603632"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575304","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":"Silencing ATF3 mediates mitochondrial homeostasis and improves ischemic stroke through regulating the MAPK signaling pathway.","authors":"Haifengqing Li, Fan Zhang, Cong Zhang, Min Zhou, Qing Liu, Guoyong Zeng","doi":"10.3389/fnmol.2025.1554802","DOIUrl":"10.3389/fnmol.2025.1554802","url":null,"abstract":"<p><p>Mitochondrial homeostasis is crucial for preventing and treatment of ischemic stroke. This study aimed to investigate the role of activating transcription factor 3 (ATF3) in ischemic stroke and mitochondrial homeostasis. ATF3 was silenced in oxygen glucose deprivation/reperfusion (OGD/R)-treated HT22 cells to evaluate its effects on cell apoptosis and mitochondrial function. The effects of silencing ATF3 on neurological injury, infarction, adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD+), mitofusin 1 (MFN1) and MFN2 were evaluated in stroke rats. Transcriptome sequencing and differential expression analysis were conducted to identify differential expressed genes (DEGs) associated with silencing ATF3, followed by functional enrichment analysis. The mitogen activated protein kinase (MAPK) agonist, anisomycin, was used to investigate the regulation of ATF3 in ischemic stroke and mitochondrial homeostasis via the MAPK pathway. Silencing ATF3 increased cell viability and inhibited apoptosis of OGD/R-induced cells. In stroke rats, silencing ATF3 reduced brain water content, decreased neurological injury and alleviated cerebral infarction. Notably, silencing ATF3 significantly inhibited the production of reactive oxygen species (ROS), increased the concentrations of ATP and NAD+, and upregulated the expression of MFN1 and MFN2. Next, 4,517 DGEs associated with silencing ATF3 were mainly enriched in MAPK signaling pathway. Silencing ATF3 downregulated the expression of phosphorylation-extracellular signal-regulated kinase (p-ERK)/ERK in OGD/R cells. Anisomycin notably reversed the effect of silencing ATF3 on ischemic stroke and mitochondrial homeostasis. Silencing ATF3 attenuates ischemic stroke and improves mitochondrial homeostasis via the MAPK signaling pathway, which shares a novel direction for maintaining mitochondrial homeostasis in ischemic stroke.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1554802"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575305","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":"Dysregulation of heterochromatin caused by genomic structural variants may be central to autism spectrum disorder.","authors":"Michael R Garvin, David Kainer","doi":"10.3389/fnmol.2025.1553575","DOIUrl":"10.3389/fnmol.2025.1553575","url":null,"abstract":"<p><strong>Introduction: </strong>Autism spectrum disorder (ASD) is a highly heritable and heterogeneous neuropsychiatric condition whose cause is still unknown. A common function of proteins encoded by reported risk-genes for ASD is chromatin modification, but how this biological process relates to neurodevelopment and autism is unknown. We recently reported frequent genomic variants displaying Non-Mendelian inheritance (NMI) patterns in family trios in two cohorts of individuals with autism. These loci represent putative structural variants (SV) and the genes that carry them participate in neurodevelopment, glutamate signaling, and chromatin modification, confirming previous reports and providing greater detail for involvement of these processes in ASD. The majority of these loci were found in non-coding regions of the genome and were enriched for expression quantitative trait loci suggesting that gene dysregulation results from these genomic disruptions rather than alteration of proteins.</p><p><strong>Methods: </strong>Here, we intersected these putative ASD-associated SVs from our earlier work with diverse genome-wide gene regulatory and epigenetic multi-omic layers to identify statistically significant enrichments to understand how they may function to produce autism.</p><p><strong>Results: </strong>We find that these loci are enriched in dense heterochromatin and in transcription factor binding sites for SATB1, SRSF9, and NUP98-HOXA9. A model based on our results indicates that the core of ASD may reside in the dysregulation of a process analogous to RNA-induced Initiation of Transcriptional gene silencing that is meant to maintain heterochromatin. This produces SVs in the genes within these chromosomal regions, which also happen to be enriched for those involved in brain development and immune response.</p><p><strong>Discussion: </strong>This study mechanistically links previously reported ASD-risk genes involved in chromatin remodeling with neurodevelopment and may explain the role of <i>de novo</i> mutations in ASD. Our results suggest that a large portion of the heritable component of autism is the result of changes in genes that control critical epigenetic processes.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1553575"},"PeriodicalIF":3.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559878","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":"Clusterin facilitates glioma progression via BCL2L1-dependent regulation of apoptotic resistance.","authors":"Qingqing Xu, Xin Liu, Yibo Zhang, Shiyu Yuan, Wenli Huang, Mingshan Pi, Qi Xiong, Hongyan Zhou, Yuran Gui, Yifan Xiao, Xiaochuan Wang, Xiji Shu, Yiyuan Xia","doi":"10.3389/fnmol.2025.1596021","DOIUrl":"10.3389/fnmol.2025.1596021","url":null,"abstract":"<p><strong>Background: </strong>Clusterin (CLU) is a multifunctional protein involved in various pathophysiological processes and diseases. Glioma, the most common aggressive primary brain tumor, is characterized by high morbidity, mortality, and extremely poor prognosis. Our research has found that CLU is upregulated in glioma and contributes to increased tumor malignancy. However, the specific regulatory mechanisms of CLU in the context of glioma are not fully understood.</p><p><strong>Methods: </strong>We used glioma public databases, immunohistochemistry (IHC), and immunoblotting techniques to evaluate the expression levels and prognostic value of CLU in glioma. Cell migration and proliferation assays, including the scratch wound healing and MTT assays, were conducted to assess the functional impact of CLU. In addition, immunoblotting and flow cytometry were used to analyze apoptosis-related proteins and CLU-BCL2L1 interactions. An <i>in situ</i> tumor model using nude mice was established to investigate the effects of CLU <i>in vivo</i>.</p><p><strong>Results: </strong>Bioinformatics analyses showed that CLU was highly expressed in glioma, associated with poor clinical outcomes. Functional assays revealed that CLU and BCL2L1 promoted glioma cell migration and proliferation. Silencing CLU reduced the migration and proliferation of glioma cells, while overexpression of CLU enhanced these aggressive phenotypes. Mechanistic studies showed CLU regulated BCL2L1 expression, inhibiting apoptosis pathways and promoting malignancy. <i>In vivo</i> experiments confirmed the inhibitory effects of CLU downregulation on glioma growth.</p><p><strong>Conclusion: </strong>This study clarifies the role of the CLU-BCL2L1 axis in promoting glioma migration and proliferation both <i>in vitro</i> and <i>in vivo</i>. It suggests that targeting this pathway may be a promising therapeutic strategy for glioma.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1596021"},"PeriodicalIF":3.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12216978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553244","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}