Brain Research Bulletin最新文献

{"title":"Expression of concern: \"Effect of perioperative preemptive analgesia on hippocampal GABAA receptor α1/α5 balance in aged mild cognitive impairment rats\" [Brain Res. Bull. 237 (2026) 111811].","authors":"","doi":"10.1016/j.brainresbull.2026.111864","DOIUrl":"10.1016/j.brainresbull.2026.111864","url":null,"abstract":"","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":" ","pages":"111864"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted inhibition of microglial C5aR1 by PMX205 mitigates post-ischemic stroke neuroinflammation and promotes functional recovery","authors":"Jie Cao ,&nbsp;Saisai Tian ,&nbsp;Zilong Deng ,&nbsp;Jin Xu ,&nbsp;Yangyang Liu ,&nbsp;Xuan Shi ,&nbsp;Lei Bai ,&nbsp;Xiang Li Jr ,&nbsp;Haiying Li","doi":"10.1016/j.brainresbull.2026.111873","DOIUrl":"10.1016/j.brainresbull.2026.111873","url":null,"abstract":"<div><h3>Background</h3><div>Ischemic stroke constitutes the leading cause of death and disability worldwide. Post-stroke neuroinflammation, a major driver of secondary neurodegeneration, has emerged as a priority therapeutic target. Microglia serve as critical initiators of this neuroinflammatory cascade in ischemic stroke. This study employed single-cell RNA sequencing and functional experiments to identify key regulatory factors in microglia following distinct ischemic stroke subtypes, with the goal of translating these findings into therapeutic targets for clinical application.</div></div><div><h3>Methods</h3><div>To identify key regulators in ischemic stroke, we mined and analyzed public single-cell RNA sequencing datasets. Two etiologically distinct stroke models were subsequently established: permanent focal ischemia via distal middle cerebral artery occlusion (dMCAO) and transient ischemia-reperfusion injury using middle cerebral artery occlusion/reperfusion (MCAO/R). <em>C5aR1</em> spatiotemporal expression was quantified through immunofluorescence (cellular localization) and quantitative immunoblotting (temporal dynamics), followed by validation of PMX205-<em>C5aR1</em> binding affinity via rigid-receptor molecular docking. Therapeutic assessment included acute-phase measurements (3d post-stroke): pro-inflammatory cytokines (ELISA), cerebral infarction volume (TTC staining), and co-quantification of neuronal apoptosis/viability (TUNEL/Nissl); alongside chronic functional recovery tracking (14d): motor coordination (rotarod), sensorimotor integration (adhesive removal test), anxiety-like behavior (open field exploration), and spatial working memory (Y-maze spontaneous alternation).</div></div><div><h3>Results</h3><div>Bioinformatics analysis identified significant upregulation of <em>C5aR1</em> in activated microglia following ischemic stroke. This finding was corroborated by spatially resolved immunofluorescence and quantitative immunoblotting; molecular docking confirmed stable PMX205-C5aR1 binding via specific hydrophobic interactions, and subsequent therapeutic intervention with PMX205 profoundly suppressed neuroinflammation (IL-1β/IL-6/TNF-α), reduced cerebral infarction, attenuated neuronal apoptosis, and reversed long-term neurological deficits.</div></div><div><h3>Conclusion</h3><div>Targeted inhibition of C5aR1 by PMX205 represents a therapeutically viable strategy to attenuate neuroinflammatory cascades and improve long-term functional recovery after ischemic stroke.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"239 ","pages":"Article 111873"},"PeriodicalIF":3.7,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637979","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 indole metabolites derived from gut microbiota in Parkinson's disease: A comprehensive review","authors":"Shuo Meng","doi":"10.1016/j.brainresbull.2026.111775","DOIUrl":"10.1016/j.brainresbull.2026.111775","url":null,"abstract":"<div><div>Emerging evidence suggests that Parkinson’s disease (PD) extends beyond the brain and involves early disturbances along the gut-brain axis. Among the metabolites shaping this communication, bacterial products derived from tryptophan, particularly indole compounds, are gaining attention as key biochemical links between intestinal dysbiosis and neurodegeneration. Multi-omics studies consistently show a reduction in commensal bacteria capable of producing beneficial indoles and an enrichment of <em>Enterobacteriaceae</em> that redirect tryptophan catabolism toward toxic intermediates. This shift disrupts epithelial and blood-brain barrier function and amplifies inflammatory and oxidative stress pathways within the central nervous system. Protective metabolites such as indole-3-propionic acid (IPA), indole-3-acetic acid (IAA), indole-3-lactic acid (ILA), and indole-3-carbinol (I3C) exert antioxidant, barrier-stabilizing, and anti-inflammatory effects through receptors including the aryl hydrocarbon and pregnane X receptors. Conversely, uremic indoles such as indoxyl sulfate (IS) and p-cresyl sulfate (pCS) activate microglia and astrocytes, promote α-synuclein aggregation, and accelerate dopaminergic neuron loss. Together, these findings support a view of PD as a metabolic imbalance between neuroprotective and neurotoxic indoles. Understanding how microbial and host pathways regulate this balance may open opportunities for early diagnosis and targeted interventions that integrate metabolism, immunity, and neuroprotection.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"237 ","pages":"Article 111775"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146154363","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 salience network, depression, and exercise dependence in middle-aged and older adults: A structural MRI study","authors":"Feifei Zhang ,&nbsp;Yingbo Shao ,&nbsp;Zhiyun Jia ,&nbsp;Xiaochun Wang","doi":"10.1016/j.brainresbull.2026.111770","DOIUrl":"10.1016/j.brainresbull.2026.111770","url":null,"abstract":"<div><h3>Background</h3><div>Exercise guidelines encourage middle-aged and older adults to engage in physical activity for its health benefits. However, continuous excessive exercise can also lead to physiological and psychological symptoms, often called exercise dependence. The precise brain pathways underlying exercise dependence and depression in older individuals remain unclear.</div></div><div><h3>Methods</h3><div>This study included 79 participants exhibiting symptoms of exercise dependence and 54 healthy participants who engaged in regular exercise without symptoms. Initially, paper-based questionnaires were used to evaluate participants' overall health and symptoms of exercise dependence. Subsequently, non-negative matrix factorization and Kullback–Leibler divergence-based similarity analysis were employed to identify structural brain networks. At the same time, a two-sample T-test was conducted to assess group differences. Finally, partial correlation and mediation analyses were performed to explore the relationships between structural networks, exercise dependence, and depression.</div></div><div><h3>Results</h3><div>The findings revealed that the gray matter volume (GMV) and internal structural connectivity of the salience network were significantly increased in the group with exercise dependence symptoms. These changes were primarily associated with three key characteristics of exercise dependence: tolerance, conflict, and time commitment. Importantly, depression was found to mediate the relationship between the salience network and exercise dependence.</div></div><div><h3>Conclusions</h3><div>In older adults, increased structural connectivity within the salience network may amplify impulsive and reward-driven cravings for exercise and the ability to perceive emotional states such as depression. These findings indicate that the salience network could serve as a potential target for preventing and treating exercise dependence in the elderly population.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"236 ","pages":"Article 111770"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149225","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 Dleu2 regulates fear extinction memory through Celf2-driven synaptic plasticity","authors":"Ziwei Pi ,&nbsp;Jiazhi Jiang ,&nbsp;Lixin Dong ,&nbsp;Ziyue Xu ,&nbsp;Yi Zhang ,&nbsp;Gaomeng Luo ,&nbsp;Junhui Liu ,&nbsp;Runming Liu ,&nbsp;Zhehao Li ,&nbsp;Sha Liu ,&nbsp;Jincao Chen ,&nbsp;Wei Wei ,&nbsp;Xiang Li","doi":"10.1016/j.brainresbull.2026.111757","DOIUrl":"10.1016/j.brainresbull.2026.111757","url":null,"abstract":"<div><div>Long noncoding RNAs (lncRNAs) are diverse regulators that shape many aspects of brain function. Nonetheless, their role in the mechanisms underlying fear extinction memory remains insufficiently explored. We profiled lncRNAs following the RNA capture-seq in the infralimbic prefrontal cortex (ILPFC) and identified the processed-transcript lncRNA deleted in lymphocytic leukemia-2 (Dleu2). The knockdown of Dleu2 by antisense oligonucleotide (ASO) impaired extinction memory, which demonstrated an essential role of Dleu2 in this process. To elucidate the underlying mechanism, CHIRP-seq and ATAC-seq analyses demonstrated an increased binding of Dleu2 within the intronic region of <em>Celf2</em>, accompanied by enhanced chromatin accessibility. This modulation subsequently promotes the transcription of <em>Celf2</em>, a critical gene involved in synaptic plasticity. Functionally, <em>Celf2</em> knockdown in ILPFC recapitulated the fear extinction memory deficit and reduced the number of dendritic spines. Together, these results indicate that lncRNA Dleu2 may serve as a potential therapeutic entry point for memory-related disorders.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"236 ","pages":"Article 111757"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional magnetic resonance-based analysis of dynamic functional connectivity in patients with olfactory impairment in Parkinson's disease","authors":"Fangling He ,&nbsp;Huihua Liu","doi":"10.1016/j.brainresbull.2026.111750","DOIUrl":"10.1016/j.brainresbull.2026.111750","url":null,"abstract":"<div><h3>Objective</h3><div>The purpose of this research is to utilize resting-state functional magnetic resonance imaging (rs-fMRI), combined with sliding-window and cluster analysis methods. To identify alterations in functional connectivity (FC) patterns in patients with Parkinson's disease who exhibit olfactory dysfunction prior to the onset of motor symptoms, compared to healthy individuals.This method is intended to improve capabilities for the early detection of PD.</div></div><div><h3>Materials and Methods</h3><div>We recruited fifteen individuals from three distinct groups: PD patients with no or mild olfactory dysfunction (PD-N/MH), those with severe olfactory dysfunction, and healthy controls (HC). We gathered and analyzed resting-state fMRI data to examine dynamic FC across these groups, subsequently conducting a thorough statistical evaluation.</div></div><div><h3>Results</h3><div>Our cluster analysis identified two unique states of brain network connections across the groups. Notably, the subgroup with PD exhibited a more frequent occurrence and extended duration in state 1, along with reduced state transitions. Notably, the severity of olfactory dysfunction was significantly correlated with increased durations and frequencies in state 1 (<em>P</em> ＜0.05).</div></div><div><h3>Conclusion</h3><div>These observations underscore the significant relationship between state 1 connectivity patterns and olfactory impairment in PD patients. The discovery that PD patients with Parkinson’s disease (PD) “linger” in the sparsely connected state 1 provides a dynamic functional correlate of the progressive pathology that initially affects olfaction. Dynamic functional connectivity analysis successfully distinguished PD patients from healthy controls even prior to the onset of motor symptoms, suggesting its potential as a neuroimaging biomarker for Parkinson's disease. Consequently, this method may facilitate early identification, timely intervention, and improved clinical management of PD by providing an early warning signal before motor symptom——based diagnosis, thereby potentially delaying disease progression and alleviating the burden on patients, families, and society.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"236 ","pages":"Article 111750"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112424","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":"Divergent effects of high-frequency rTMS on cognitive performance in sleep-deprived nurses: An EEG brain network study","authors":"Sujie Wang ,&nbsp;Mengru Xu ,&nbsp;Linze Qian ,&nbsp;Lingyun Gao ,&nbsp;Yu Sun","doi":"10.1016/j.brainresbull.2026.111772","DOIUrl":"10.1016/j.brainresbull.2026.111772","url":null,"abstract":"<div><h3>Background:</h3><div>Sleep deprivation (SD) is a common occupational hazard, particularly for shift workers like nurses, leading to significant impairments in cognitive functions such as sustained attention and working memory. High-frequency repetitive transcranial magnetic stimulation (rTMS) is a promising neuromodulation technique for cognitive enhancement, but its effects in sleep-deprived individuals and the underlying neural mechanisms remain poorly understood. This study aimed to investigate the efficacy of high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) in modulating sustained attention and working memory after a night shift and to explore the associated changes in brain network topology.</div></div><div><h3>Methods:</h3><div>In a within-subject design, 28 healthy female night-shift nurses participated in two experimental sessions after a night of work: one with real 5 Hz rTMS and one with sham rTMS applied to the left DLPFC. Following stimulation, participants performed a psychomotor vigilance task (PVT) and a 2-back task while their electroencephalography (EEG) data were recorded. Behavioral performance (reaction time and accuracy) and subjective fatigue were assessed. Graph theory analysis was applied to the EEG data to evaluate changes in functional brain network topology at both global and nodal levels.</div></div><div><h3>Results:</h3><div>Real rTMS significantly reduced subjective mental fatigue compared to sham stimulation. However, the behavioral effects were task-dependent. For the 2-back task, real rTMS led to a significant impairment in performance, characterized by slower reaction times and lower accuracy. For the PVT, there was a non-significant trend towards improved performance. These behavioral outcomes were mirrored by distinct patterns of network reorganization. During the PVT, real rTMS induced decreased functional segregation (lower clustering coefficient and local efficiency) in the alpha band. Conversely, during the 2-back task, it resulted in increased functional segregation and small-worldness in the theta band.</div></div><div><h3>Conclusion:</h3><div>High-frequency rTMS over the left DLPFC exerts differential, task-specific effects on cognitive function in a sleep-deprived state. The impairment in working memory, despite a network configuration theoretically supportive of local processing, likely results from an inverted-U effect, where the rTMS pushed an already strained and compensating brain system past its optimal level of cortical excitability. The findings highlight the critical role of both baseline brain state and specific cognitive demands in determining the outcomes of neuromodulation, providing crucial insights for the targeted application of rTMS to mitigate cognitive deficits from sleep deprivation.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"236 ","pages":"Article 111772"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164100","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":"Stressed minds, altered strategies: Acute stress impairs proactive control in table tennis athletes","authors":"Lin Xu ,&nbsp;Ziyi Peng ,&nbsp;Jie Lian ,&nbsp;Xinxin Gong ,&nbsp;Yongcong Shao ,&nbsp;Mengfei Han ,&nbsp;Fubin Jiao","doi":"10.1016/j.brainresbull.2026.111766","DOIUrl":"10.1016/j.brainresbull.2026.111766","url":null,"abstract":"<div><h3>Background</h3><div>Intense stress greatly affects athletes’ mental state and performance, and cognitive control, which is vital for handling unexpected situations and maintaining peak performance. Although previous research has shown that acute stress can impact different aspects of cognitive control, the exact mechanisms and effects are still debated. This study aimed to investigate how acute stress impacts proactive and reactive control in table tennis players, providing new insights into the intricate role of stress in athletes’ cognitive control.</div></div><div><h3>Methods</h3><div>Acute stress was induced in 25 male table tennis athletes using the Maastricht Acute Stress Task (MAST). Behavioral and electroencephalogram (EEG) data were recorded before and after acute stress exposure. The EEG data included both resting-state and task-related recordings. Functional connectivity analysis was conducted on the resting-state EEG data. Event-related potential (ERP) analysis was conducted on the task-related EEG data recorded during the AX-Continuous Performance Task (AX-CPT).</div></div><div><h3>Results</h3><div>The behavioral results showed similar reaction times in table tennis athletes before and after acute stress, with AY trials showing significantly higher accuracy. The ERP results revealed a decrease in contingent negative variation (CNV) amplitude and increased N2 component but no significant difference was observed between the P3b and P3a components before and after acute stress. Functional connectivity analysis showed that acute stress activated the visual network and enhanced functional connectivity with multiple brain regions.</div></div><div><h3>Conclusion</h3><div>Acute stress induces large-scale activation of visual and salience networks while affecting the two modes of cognitive control, with reactive control predominating over proactive control. The weakening of proactive control by acute stress affected response preparation rather than pre-attention and stimuli processing, while the enhancement of reactive control resulted increased detection and monitoring of conflicting information. These findings shed light on how acute stress induces a neurocognitive shift in athletes, contributing to the advancement of the Dual Mechanisms of Cognitive Control (DMC) framework. This shift highlights the critical balance between proactive and reactive control under stress, offering valuable insights for developing interventions that optimize athletes’ performance under high-pressure conditions.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"236 ","pages":"Article 111766"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131510","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 central amygdala as a pathological hub: A multi-level review of pain–emotion comorbidity","authors":"Xiaohu Xu ,&nbsp;Jiaqi Hu ,&nbsp;Yaxuan Wang ,&nbsp;Yanyan Zhu ,&nbsp;Yuwei Cao ,&nbsp;Man Li ,&nbsp;Ping Peng","doi":"10.1016/j.brainresbull.2026.111756","DOIUrl":"10.1016/j.brainresbull.2026.111756","url":null,"abstract":"<div><div>Chronic pain frequently coexists with emotional disorders such as anxiety and depression, thereby imposing a considerable global burden. This review aims to establish the central amygdala (CeA) as the primary neural hub regulating pain-related comorbidities. Existing evidence demonstrates that the CeA shapes both the sensory-discriminative and emotional-motivational dimensions of pain by integrating ascending pain inputs and descending regulatory outputs. At the cellular level, functionally antagonistic GABAergic neuronal populations within the central lateral capsular division (CeLC) exhibit abnormal plasticity during chronic pain, which disrupts emotional homeostasis. Key molecular mechanisms within the CeA include neuropeptide signaling, regulation of ionotropic and metabotropic glutamate receptors, and opioid receptor dynamics, all of which often display lateralization and state dependence. Moreover, neuroimmune dysregulation within the CeA and epigenetic modifications contribute substantially to the persistence of pain–emotion comorbidities. By integrating evidence across neural circuits, cells, molecules, immune responses, and epigenetics, this multi-level review positions the CeA as a critical convergence point and promising therapeutic target for alleviating the intertwined suffering of chronic pain and emotional disorders.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"236 ","pages":"Article 111756"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146104049","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 transcriptomic analysis reveals mitochondrial dysregulation and macrophage heterogeneity associated with MTHFD2 in glioblastoma","authors":"Binfeng Tu ,&nbsp;Yulong Ji ,&nbsp;Zilong Tan ,&nbsp;Shiqi Cheng ,&nbsp;Yan Zhang","doi":"10.1016/j.brainresbull.2026.111758","DOIUrl":"10.1016/j.brainresbull.2026.111758","url":null,"abstract":"<div><h3>Background</h3><div>Glioblastoma (GBM) is an aggressive brain tumor with therapeutic resistance and poor prognosis. Mitochondrial dysfunction has emerged as a critical driver of tumor progression and immune modulation, yet mitochondrial gene alterations and their cellular specificity in GBM remain unclear.</div></div><div><h3>Methods</h3><div>Transcriptomic datasets (TCGA-GBM, GSE66354) were analyzed to identify differentially expressed mitochondria-associated genes using MitoCarta3.0. Prognostic mitochondrial DEGs (MitoDEGs) were determined by Cox regression, and a nomogram was constructed for survival prediction. Single-cell RNA sequencing was applied to explore mitochondrial gene expression in cellular populations, particularly macrophages. Functional enrichment and pseudotime analyses were conducted to define macrophage subpopulations, while in vitro assays validated the role of MTHFD2 in glioblastoma cell behavior, macrophage migration and the expression of IL-6 and CCL2.</div></div><div><h3>Results</h3><div>MTHFD2 was identified as a diagnosis mitochondrial hub gene strongly correlated with GBM diagnosis. Single-cell analysis revealed elevated mitochondrial activity and MTHFD2 expression in tumor-associated macrophages. A distinct MTHFD2-high macrophage subpopulation displayed immune-activated and metabolically reprogrammed pathways, representing a terminally differentiated state linked to tumor progression. Functional assays showed that silencing MTHFD2 suppressed glioblastoma cell proliferation, invasion, colony formation, and reduced macrophage migration and the expression of IL-6 and CCL2.</div></div><div><h3>Conclusion</h3><div>Mitochondrial dysfunction mediated by MTHFD2 in macrophages plays a key role in GBM progression and immune heterogeneity. MTHFD2 represents a potential diagnostic biomarker and therapeutic target for modulating GBM immune infiltration.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"236 ","pages":"Article 111758"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146104046","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}