Frontiers in Molecular Neuroscience最新文献

{"title":"SST interneuron maturation extends beyond the second postnatal week and is driven by coordinated transcriptional and functional remodeling.","authors":"Ourania Christodoulou, Konstantinos Diskos, Angeliki Velli, Panagiotis Moulos, Kyriaki Sidiropoulou, Myrto Denaxa","doi":"10.3389/fnmol.2026.1892850","DOIUrl":"10.3389/fnmol.2026.1892850","url":null,"abstract":"<p><p>Cortical somatostatin-expressing (SST+) interneurons (cINs) are key regulators of dendritic integration and synaptic plasticity, yet the timing and molecular mechanisms underlying their postnatal maturation remain incompletely understood. Previous studies have suggested that key aspects of SST+ cIN maturation are largely established by the end of the second postnatal week. Here, we combined transcriptomic profiling and electrophysiological recordings to characterize the developmental trajectory of SST+ interneurons in the mouse neocortex from the second postnatal week through the end of the first postnatal month. Bulk RNA sequencing of fluorescence-activated cell sorted SST+ cINs at P10, P15, and P30 revealed extensive transcriptional remodeling, including continued upregulation of genes associated with ion channel activity, synaptic transmission, and neuronal excitability beyond the second postnatal week. Consistent with these molecular changes, electrophysiological recordings demonstrated ongoing maturation of intrinsic and synaptic properties between P15 and P30. Notably, developmental upregulation of voltage-gated sodium and potassium genes correlated with the observed changes in intrinsic excitability, while alterations in GABA _<i>A</i> receptor subunit expression paralleled the maturation of inhibitory synaptic transmission. Computational modeling incorporating these transcriptional changes recapitulated the electrophysiological differences between P15 and P30 SST+ cINs. Together, our findings demonstrate that SST+ cIN maturation is not complete by the second postnatal week but instead continues through later postnatal stages, revealing a prolonged and coordinated transcriptional and physiological program underlying their functional integration into cortical circuits.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1892850"},"PeriodicalIF":4.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080155","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":"Extracellular matrix and perineuronal nets in neural plasticity, memory, and epileptogenesis.","authors":"Hanxiao Zhu, Qiongfen Li, Yun Li, Wei Wang","doi":"10.3389/fnmol.2026.1945520","DOIUrl":"10.3389/fnmol.2026.1945520","url":null,"abstract":"<p><p>In the mature brain, the extracellular matrix (ECM) molecules derived from neurons and glia accumulate in spatially distinct extracellular compartments, including a diffuse interstitial matrix and condensed perineuronal nets (PNNs), where they regulate receptor mobility, ion homeostasis, cell-surface signaling, structural stabilization, and experience-dependent synaptic remodeling. PNNs, in particular, assemble around selected neuronal populations - most prominently parvalbumin-positive fast-spiking interneurons - and thereby couple extracellular molecular architecture to inhibitory control, critical-period closure, and the long-term precision of network activity. These properties place ECM and PNNs at the intersection of developmental maturation, synaptic plasticity, memory-related stabilization, and pathological circuit remodeling. These principles are directly relevant to epilepsy. If ECM and PNNs normally stabilize synaptic organization, preserve inhibitory interneuron function, regulate extracellular space, and constrain maladaptive rewiring, then their disruption is positioned to lower the threshold for persistent hyperexcitability and aberrant network synchronization. For instance, hyaluronan deficiency alters neuronal activity and can produce seizures. However, the biological mechanisms and specific contributions of ECM and PNN in epilepsy still need to be further elucidated. Therefore, the purpose of the study is to systematically elaborate on the similarities and differences between ECM and PNN in terms of plasticity, memory, the biological mechanisms of neurological diseases, especially in the context of epilepsy.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1945520"},"PeriodicalIF":4.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080724","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":"Association between presbycusis and cognitive function: contributing factors in older adult.","authors":"Duo Wei, Yuehong Chen, Bin Liu, Zhiqiang Tan","doi":"10.3389/fnmol.2026.1820873","DOIUrl":"10.3389/fnmol.2026.1820873","url":null,"abstract":"<p><strong>Background and objectives: </strong>This cross-sectional study investigated the association between presbycusis (PC) and cognitive function in older adults and identified factors influencing cognitive performance.</p><p><strong>Materials and methods: </strong>A total of 126 participants ( ≥ 60 years) were enrolled, including 58 with PC and 68 controls with normal hearing. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Statistical analyses included <i>t</i>-tests, chi-square tests, Spearman's correlation, and binary logistic regression.</p><p><strong>Results: </strong>MMSE scores declined significantly with age in both groups (PC: <i>r</i> = -0.585; control: <i>r</i> = -0.572, both <i>p</i> < 0.001). In the PC group, lower MMSE scores correlated with higher pure-tone average (<i>r</i> = -0.563, <i>p</i> < 0.01) and poorer speech recognition (<i>r</i> = 0.365, <i>p</i> = 0.01). Logistic regression identified higher education as an independent protective factor against cognitive impairment (OR = 0.162, 95% CI: 0.031-0.842, <i>p</i> = 0.021), whereas greater hearing loss severity (OR = 1.083, 95% CI: 1.001-1.172, <i>p</i> = 0.046) and longer hearing loss duration (OR = 0.778, 95% CI: 0.646-0.937, <i>p</i> = 0.008) were associated with increased odds of cognitive impairment. Age and sex were not significant.</p><p><strong>Conclusions: </strong>Greater hearing loss severity, poorer speech recognition, and longer hearing loss duration are associated with lower cognitive function, while higher education is protective. These findings support the close interrelationship between auditory and cognitive health in older adults, suggesting that early audiological assessment and hearing rehabilitation may aid cognitive health, though causality requires longitudinal validation.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1820873"},"PeriodicalIF":4.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080639","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":"Peripheral exosomal miRNAs as candidate molecular indicators associated with acupuncture at ST36 in an LPS-induced neuroinflammation model.","authors":"Seung-Nam Kim","doi":"10.3389/fnmol.2026.1917472","DOIUrl":"10.3389/fnmol.2026.1917472","url":null,"abstract":"<p><p>This study aimed to identify circulating exosomal microRNA (miRNA) candidates showing a control-like expression pattern following ST36 acupuncture treatment in an LPS-induced neuroinflammation model, using empirical Bayes reanalysis of previously published microarray data. Two independent Affymetrix GeneChip miRNA 4.0 microarray datasets from C57BL/6 male mice were reanalysed using the limma empirical Bayes framework with Benjamini-Hochberg false discovery rate (FDR) correction. After detection-call filtering, 286 commonly expressed probes were identified. Control-like pattern candidates were defined by three criteria: FDR < 0.05 for the LPS effect, FDR > 0.05 for the LPS+ST36 vs CON comparison, and logFC direction opposite to the LPS effect. Target gene prediction and pathway enrichment were subsequently performed. Eight miRNA candidates were identified: five upregulated by LPS and showing a control-like pattern following ST36 (let-7d-5p, miR-103-3p, miR-107-3p, miR-451a, miR-7047-5p) and three downregulated by LPS and showing a control-like pattern following ST36 (miR-5128, miR-16-2-3p, miR-101a-5p). None overlapped with candidates from the original fold-change-based analysis. Functional enrichment of 1,596 predicted target genes revealed significant enrichment in MAPK, PI3K-Akt, and Wnt signaling pathways, with Gene Ontology analysis highlighting convergence on neuronal and synaptic processes. Limma-based reanalysis reveals a distinct set of ST36-associated exosomal miRNAs overlooked by threshold-based approaches, providing exploratory candidate molecular indicators for further investigation of acupuncture's peripheral effects in neuroinflammation.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1917472"},"PeriodicalIF":4.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080660","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":"Mitohormesis linking metabolic dysfunction and neurodegeneration: implications for dementia and therapeutic strategies.","authors":"Toshiki Otoda, Hideto Nakajima, Tadateru Takayama","doi":"10.3389/fnmol.2026.1892506","DOIUrl":"10.3389/fnmol.2026.1892506","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Mitochondria are central regulators of cellular metabolism, redox homeostasis, and stress adaptation. Mitohormesis refers to an adaptive response in which mild or transient mitochondrial perturbation activates stress-response pathways that subsequently enhance mitochondrial or cellular resilience; however, persistent or excessive stress can overwhelm adaptive capacity and promote mitochondrial dysfunction and tissue injury. Metabolic diseases, including obesity and type 2 diabetes mellitus, are major risk factors for cognitive decline and dementia, and clinical studies have demonstrated associations between metabolic dysfunction, structural brain abnormalities, accelerated brain aging, and impaired cognitive function. However, direct evidence linking mitochondrial dysfunction to neurodegeneration in humans remains limited, with most mechanistic insights derived from experimental animal models and cultured neuronal systems. Experimental evidence indicates that chronic metabolic stress can disrupt mitochondrial quality control and proteostasis, increase mitochondrial reactive oxygen species production, and promote neuroinflammation and neuronal dysfunction. Conversely, adaptive mitochondrial stress responses can preserve mitochondrial integrity and cellular resilience through coordinated regulation of the integrated stress response, mitochondrial quality-control mechanisms, lysosomal-mitochondrial crosstalk, extracellular vesicle-mediated communication, and inter-organ signaling. In Alzheimer's disease, mitochondrial dysfunction and amyloid-β/tau pathology may interact bidirectionally, potentially generating self-reinforcing cycles of neuronal injury. Lifestyle and pharmacological interventions-including exercise; caloric restriction; nutritional ketosis; and the use of metformin, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists-have been associated with adaptive mitochondrial and metabolic responses involving AMP-activated protein kinase, nuclear factor erythroid 2-related factor 2, mitochondrial biogenesis, mitophagy, and redox signaling. However, evidence that mitohormesis directly mediates their beneficial effects varies substantially across interventions and remains predominantly indirect or hypothesized in humans. Moreover, the discrepancy between encouraging preclinical findings and clinical outcomes highlights important translational barriers, including the lack of validated biomarkers, uncertainty regarding optimal stress intensity and timing, and tissue- and disease-specific differences in adaptive capacity. Collectively, current evidence supports mitohormesis as a conceptual framework for integrating mitochondrial stress adaptation, metabolic dysfunction, and neuronal resilience rather than as an established unifying mechanism underlying neurodegeneration. Defining the conditions under which mitochondrial stress is adaptive, identifying reliable biomarkers of mitohormesis, and determining whe","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1892506"},"PeriodicalIF":4.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080699","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":"Aging, the microbiota-gut-brain axis, and late-life epilepsy: a hypothesis-driven review.","authors":"Yingsi Cao, Huiying Li, Minzheng Xu, Yuting Teng","doi":"10.3389/fnmol.2026.1861519","DOIUrl":"10.3389/fnmol.2026.1861519","url":null,"abstract":"<p><p>Late-life epilepsy is an increasingly important neurological and public health challenge, yet its biological basis remains incompletely understood. The microbiota-gut-brain axis has emerged as a systems-level framework linking peripheral metabolism, barrier integrity, immune signaling, and brain excitability. Growing evidence supports an association between gut dysbiosis and epilepsy, particularly drug-resistant epilepsy, although direct evidence specifically addressing this axis in late-life epilepsy remains limited. Most available data instead come from aging biology, general epilepsy cohorts, pediatric populations, and preclinical models. This review considers how aging may reshape the microbiota-gut-brain axis in ways relevant to epilepsy in older adults. We summarize aging-related remodeling of this axis, including gut dysbiosis, impaired intestinal and blood-brain barrier/neurovascular unit homeostasis, loss of protective microbial metabolites, chronic low-grade inflammation, and neuroimmune priming. We then review clinical, functional, and mechanistic evidence linking microbiota-related abnormalities to epilepsy, with emphasis on broad ecological imbalance, barrier dysfunction, neuroinflammatory signaling, short-chain fatty acid pathways, and vagal gut-brain communication. On this basis, we propose that aging may increase the likelihood that epilepsy-associated microbiota-gut-brain axis abnormalities translate into persistent peripheral inflammation, BBB/NVU vulnerability, amplified neuroinflammation, and reduced neural network resilience, thereby increasing seizure susceptibility. We further discuss microbiota-targeted interventions, including ketogenic diet, probiotics and prebiotics, fecal microbiota transplantation, and metabolite-based strategies, as hypothesis-informed translational directions rather than established therapies for late-life epilepsy. Overall, we suggest that the microbiota-gut-brain axis functions as a context-dependent modifier of vulnerability in late-life epilepsy and provides a useful framework for guiding future age-stratified, biomarker-oriented, and etiology-aware studies.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1861519"},"PeriodicalIF":4.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074432","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":"Electroacupuncture alleviates inflammatory pain by modulating the CXCL1/CXCR2 signaling axis in the spinal cord dorsal horn of rats.","authors":"Xiazhen Xu, Ziyan Fang, Kaihua Song, Yang Shen, Chenxin Jiang, Mengchao Xu, Shouhai Hong","doi":"10.3389/fnmol.2026.1880288","DOIUrl":"10.3389/fnmol.2026.1880288","url":null,"abstract":"<p><strong>Aims: </strong>To elucidate the function of the C-X-C motif chemokine ligand 1 (CXCL1)-C-X-C Motif Chemokine Receptor 2 (CXCR2) signaling axis within the Spinal Cord Dorsal Horn (SCDH) in mediating the antinociceptive effects of electroacupuncture (EA) on pain.</p><p><strong>Main methods: </strong>An inflammatory pain model was created by injecting 0.1 ml of Complete Freund's Adjuvant into the right foot of Wistar rats. EA was then applied daily for 7 days at the Zusanli and Kunlun points, using a 2/100 Hz wave pattern and gradually increasing the current from 0.5 mA to 1.5 mA. Pain thresholds were measured, and effective pain relief was confirmed. The spinal dorsal horn was analyzed for CXCL1 content via ELISA, CXCR2 expression via Western blotting, and gene expression via PCR. Intrathecal catheterization was used to administer recombinant CXCL1 or the CXCR2 antagonist SB225002 to study their effects on EA's pain relief.</p><p><strong>Key findings: </strong>(1) Electroacupuncture demonstrates substantial analgesic effects in rats experiencing inflammatory pain, notably increasing the thermal and mechanical pain thresholds in the plantar region of the affected limb. (2) Findings from enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) analyses reveal that, EA significantly downregulates the protein levels of CXCL1 and CXCR2 in the dorsal horn of the spinal cord in rats with inflammatory pain, and decreases the expression levels of the inflammatory cytokine IL-1β in serum.(3) PCR results indicated that EA significantly reduced CXCL1 and CXCR2 mRNA levels in the spinal cord's dorsal horn, highlighting its gene regulatory effect. (4) Subsequent pretreatment with recombinant CXCL1 protein counteracted the analgesic effects of EA. In contrast, intrathecal administration of the CXCR2 antagonist SB225002 replicated these effects and led to a significant reduction in serum IL-1β levels. (5) Finally, the administration of recombinant CXCL1 and CXCR2 antagonists substantiated that CXCL1 and CXCR2 serve as pivotal regulatory targets for the analgesic effects of EA. The upregulation of CXCL1 diminishes these effects, whereas the antagonism of CXCR2 amplifies them.</p><p><strong>Significance: </strong>Electroacupuncture alleviates chronic inflammatory pain in rats by targeting the CXCL1-CXCR2 signaling axis in the SCDH, reducing CXCL1, CXCR2, and serum IL-1β levels, making it a potential therapeutic target.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1880288"},"PeriodicalIF":4.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060151","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":"Cognitive-behavioral phenotypes in <i>FMR1</i> premutation carriers: a cross-population comparison with mild cognitive impairment.","authors":"Nell Maltman, Jessica Greenlee, Kimberly D Mueller, Barbara B Fransway, James T Shira, Davina Hammann, Sumi Lee, Hyeri Lee, Ali Naderi Malek","doi":"10.3389/fnmol.2026.1943587","DOIUrl":"10.3389/fnmol.2026.1943587","url":null,"abstract":"<p><strong>Introduction: </strong>Carriers of the <i>FMR1</i> premutation are at risk for cognitive decline, though premutation-specific markers of age-related risk are largely unknown. One approach to determining relevant risk markers is to assess cross-population comparisons with individuals with known clinical trajectories.</p><p><strong>Methods: </strong>The present study evaluated a cross-sectional sample of male and female <i>FMR1</i> premutation carriers and controls in comparison to a longitudinal sample of individuals with known progression to mild cognitive impairment (MCI) within an enriched cohort of individuals at risk for Alzheimer's Disease and Related Dementias (ADRD) to assess potential similarities across cognitive-behavioral and genetic features. Both participant samples completed measures of working memory (digit span), language (verbal fluency, narrative elicitation), and depression. Exploratory analyses evaluated the role of <i>FMR1</i> CGG repeat length and <i>APOE</i> on cognitive-linguistic phenotypes.</p><p><strong>Results: </strong>Findings suggest that premutation carriers and controls largely differed from MCI groups across measures; however, a subgroup of premutation carriers (according to T-MoCA performance) evidenced a distinct profile characterized by differences in depression and language. No effects of CGG repeat length or <i>APOE</i> were observed in the premutation sample.</p><p><strong>Discussion: </strong>This study generates preliminary evidence for a possible risk profile of <i>FMR1</i> premutation carriers, with important implications for longitudinal studies evaluating the progression of cognitive decline.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1943587"},"PeriodicalIF":4.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038122","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":"Copper-regulated cell death after spinal cord injury: evidence boundaries for non-coding RNA, epigenetics and cuproptosis.","authors":"Jun Tao, Guobing Wang, Guoying Jiang, Wenqi Feng","doi":"10.3389/fnmol.2026.1885261","DOIUrl":"10.3389/fnmol.2026.1885261","url":null,"abstract":"<p><strong>Background: </strong>Spinal cord injury (SCI) initiates a secondary-injury cascade involving mitochondrial dysfunction, metal dyshomeostasis, neuroinflammation, and regulated cell death. Cuproptosis, a copper-dependent form of regulated cell death driven by lipoylated mitochondrial protein aggregation, has reframed copper dyshomeostasis as a potential molecular vulnerability rather than a passive trace-metal disturbance.</p><p><strong>Main body: </strong>This targeted narrative review critically synthesizes the FDX1-lipoylation-DLAT/DLST cuproptosis pathway, copper trafficking and redistribution after SCI, and the evidence boundary between spinal cord ischemia-reperfusion injury (SCIRI) and traumatic SCI. We evaluate two distinct but interacting regulatory layers: non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, circular RNAs, and extracellular-vesicle RNAs; and epigenetic regulation, including DNA methylation, histone modifications, and RNA modifications. Evidence is graded to distinguish established canonical biochemistry, the strongest direct preclinical mechanistic evidence in spinal-cord models, associative or hypothesis-generating traumatic-SCI evidence, non-SCI mechanistic validation, and testable hypotheses.</p><p><strong>Conclusion: </strong>At present the ncRNA-epigenetics-cuproptosis axis represents a molecular-neurobiological framework that still requires experimental validation rather than a clinically actionable pathway. The highest-priority next step is temporally and spatially resolved traumatic SCI validation that combines copper mapping, cell-type-specific cuproptosis execution assays, immune profiling, and genetic or pharmacological rescue experiments.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1885261"},"PeriodicalIF":4.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038063","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":"Palmitoylation-related lncRNAs link molecular signaling, immune remodeling, and tumor progression in glioma: prognostic modeling and functional validation of LYRM4-AS1.","authors":"Juan Xu, Chen Zhang, Lingling Pu, Xiaoyang Zhu, Xiaoan Sheng, Juanjuan Dong, Miaomiao Song, Chao Wang","doi":"10.3389/fnmol.2026.1901839","DOIUrl":"10.3389/fnmol.2026.1901839","url":null,"abstract":"<p><strong>Background: </strong>Glioma is a molecularly heterogeneous tumor of the central nervous system with variable clinical behavior, immune contexture, and therapeutic response. Palmitoylation is a reversible lipid modification that regulates membrane localization, synaptic signaling, inflammatory pathways, and oncogenic signaling; however, the prognostic and functional relevance of palmitoylation-related long non-coding RNAs (PRlncRNAs) in glioma remains incompletely defined.</p><p><strong>Methods: </strong>Transcriptomic and clinical data for 429 glioma patients were obtained from TCGA. Thirty palmitoylation-related genes were used to identify PRlncRNAs through co-expression analysis. A prognostic signature was constructed using univariate Cox regression, LASSO-Cox regression, and multivariate Cox regression. The model was evaluated by Kaplan-Meier analysis, ROC curves, time-dependent ROC analysis, Cox regression, C-index analysis, nomogram modeling, calibration curves, and an institutional clinical cohort of 46 paired glioma and adjacent tissues. Functional enrichment, immune deconvolution, tumor microenvironment scoring, TIDE-based immunotherapy prediction, TMB/MSI analysis, and pRRophetic-based drug-sensitivity analysis were performed. U87 and U251 glioma cells, LYRM4-AS1 knockdown, <i>in vitro</i> functional assays, and nude-mouse xenografts were used for biological validation.</p><p><strong>Results: </strong>A six-PRlncRNA signature consisting of POLR2J4, LYRM4-AS1, BX640514.2, AL592295.6, AL390755.1, and AC018730.1 stratified glioma patients into high- and low-risk groups with significantly different overall survival. The risk score remained an independent prognostic factor and showed strong predictive performance for 1-, 3-, and 5-year survival. Risk-associated genes were enriched in extracellular matrix organization, leukocyte-mediated immunity, neuroactive ligand-receptor interaction, MAPK signaling, cytokine-receptor interaction, cell-cycle programs, and ECM-receptor interaction. High-risk tumors displayed increased stromal, immune, and ESTIMATE scores, higher expression of multiple immune checkpoint genes, higher TIDE scores, and elevated TMB/MSI levels. Clinical validation confirmed differential expression of the six PRlncRNAs and the prognostic value of the risk score. Functionally, LYRM4-AS1 knockdown inhibited glioma cell proliferation, EdU incorporation, migration, invasion, and colony formation, while suppressing xenograft growth, increasing TUNEL-positive apoptotic cells, and reducing Ki-67, CD31, and MMP9 expression.</p><p><strong>Conclusion: </strong>This study identifies a palmitoylation-related lncRNA signature that integrates molecular signaling, immune remodeling, and prognosis in glioma. LYRM4-AS1 acts as a functional driver of glioma progression and may represent a candidate biomarker and therapeutic target at the crossroads of neural tumorigenesis and immune-microenvironmental regulation.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1901839"},"PeriodicalIF":4.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038059","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}