Molecular Neurobiology最新文献

{"title":"Silibinin Alleviates Cognitive Dysfunction, Biochemical Alterations, and Hippocampal Structural Changes Induced by 5 days of Sleep Deprivation with or Without a Subsequent 24-H Recovery in Rats.","authors":"Dalia Fathy El Agamy, Eman Shehata El-Roghy, Esam Omar Hendia, Omnia Mohamed Abo Said, Ahmed Mohamed Gaafer","doi":"10.1007/s12035-026-06195-y","DOIUrl":"https://doi.org/10.1007/s12035-026-06195-y","url":null,"abstract":"<p><p>Sleep deprivation (SD) impairs cognitive function through oxidative stress, neuroinflammation, and neuroendocrine dysregulation, whereas recovery sleep may not fully reverse these alterations. Silibinin possesses antioxidant, anti-inflammatory, and neuroprotective properties; however, its potential to facilitate recovery following prolonged SD remains unclear. This study investigated the effects of silibinin on cognitive dysfunction and hippocampal alterations induced by 5 days of SD, with or without a subsequent 24-h recovery period, in rats. Forty-eight adult male rats were allocated to control (n = 16), SD (n = 8), SD + recovery (n = 8), SD + silibinin (n = 8), and SD + silibinin + recovery (n = 8) groups. Cognitive performance was assessed using the Open Field Test, Morris Water Maze, and Y-Maze. Serum oxidative stress (MDA and SOD), inflammatory (TNF-α and IL-6), and hormonal biomarkers were evaluated. Hippocampal BDNF and CaMKII levels, histopathological changes, and the immunohistochemical expression of PCNA, synaptophysin, and GFAP were also assessed. SD significantly impaired cognitive performance (P < 0.05), increased oxidative stress and inflammatory cytokines (P < 0.01), altered stress-related hormones (P < 0.05), decreased hippocampal BDNF and CaMKII levels (P < 0.001) and induced marked histopathological and immunohistochemical changes. A 24-h recovery period partially ameliorated these alterations. Silibinin treatment significantly attenuated the SD-induced behavioral, biochemical, hormonal, histopathological, and immunohistochemical alterations (P < 0.05), with further improvement following recovery sleep (P < 0.05), restoring most parameters to levels comparable to those of the control group. These findings suggest that silibinin protects against SD-induced cognitive dysfunction and hippocampal injury by attenuating oxidative stress, neuroinflammation, and neuroendocrine disturbances while enhancing recovery during subsequent recovery sleep.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urban PM_0.2 Affects Astrocytes by Inducing Xenobiotic and Oxidative Stress Responses.","authors":"Liudmila Saveleva, Alexey Afonin, Mariia Ivanova, Michal Sima, Zdenek Krejcik, Tarja Malm, Pasi I Jalava, Pavel Rössner, Katja M Kanninen","doi":"10.1007/s12035-026-06232-w","DOIUrl":"https://doi.org/10.1007/s12035-026-06232-w","url":null,"abstract":"<p><p>Air pollution is the largest environmental risk factor contributing substantially to global mortality rates. Several studies demonstrated that pollutant exposure leads to neuroinflammation and oxidative stress, yet little is known about the effects induced in specific brain cell types. Here, we aimed to decipher how nanoscale particulate matter (PM_0.2, an aerodynamic diameter < 0.2 µm) collected from urban air affects a central element of the brain's homeostatic system - the astrocytes, via 24-h exposure of primary astrocyte cultures to PM_0.2 at a final concentration of 50 µg/ml. We combined transcriptomic and proteomic profiling to elucidate astrocyte-intrinsic responses to PM. PM_0.2 exposure altered the expression of 2217 mRNA, with the robust induction of xenobiotic metabolism, the Nrf2 oxidative stress response, and glutathione-mediated detoxification. Strong upregulation of cytochrome P450 genes, glutathione S-transferase superfamily, Nqo1, Ahrr and Slc17a8 was detected. Exploratory proteomic analysis identified 354 proteins with nominal evidence of altered abundance, 142 of which showed corresponding significant mRNA changes. The cross-platform-supported candidates were consistent with coordinated activation of xenobiotic-metabolism and redox-homeostasis pathways. Reanalysis of published RNA-seq datasets showed that, in contrast to PM-exposed microglia, which predominantly activate pro-inflammatory signaling pathways, astrocytes preferentially engage detoxification and antioxidant programs, while sharing a subset of stress and signaling pathways with the PM-exposed cerebral cortex in in vivo model. Our results provide insight into astrocyte-specific responses to urban air pollutant exposure and allow a better understanding of the processes activated by PM exposure in the brain.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Unified Framework for Spinal Cord Injury Repair: Metabolic-Nutritional Microenvironment Remodeling, Immune Modulation, and Neural Regeneration.","authors":"Jiangyou Shi, Qi-Lin Pan, Ning Liu, Liping Liu","doi":"10.1007/s12035-026-06239-3","DOIUrl":"10.1007/s12035-026-06239-3","url":null,"abstract":"<p><p>Spinal cord injury (SCI), as a severe central nervous system injury, often leads to permanent neurological deficits, posing significant challenges to clinical treatment. In recent years, the reconstruction of the metabolic-nutritional microenvironment has been widely recognized as a crucial breakthrough for promoting nerve repair in SCI. This microenvironment encompasses multidimensional changes, such as metabolic regulation, nutritional factor supply, and mitochondrial energy metabolism, and plays a key regulatory role in inflammatory responses and cellular metabolic adaptation through coupling with the gut-spinal cord axis and immune cell metabolic reprogramming. Although related research has advanced significantly, the spatiotemporal dynamic characteristics and underlying mechanisms of the metabolic-nutritional microenvironment in SCI repair remain incompletely elucidated. This article systematically reviews the fundamental concepts of the metabolic-nutritional microenvironment and its dynamic changes during the acute, subacute, and chronic phases of SCI, focusing on the mechanisms governing neurogenesis, axonal growth, neural stem cell fate determination, and functional rehabilitation. Based on this, from multiple levels including mitochondrial energy metabolism, supply of nutritional factors, and the gut-spinal cord axis, we propose an integrated intervention framework of \"metabolic-nutritional microenvironment reconstruction-inflammation relief-neurogenesis\" and focus on specific strategies such as metabolism-targeted drugs, nutritional interventions, and microenvironment engineering (hydrogels, conductive scaffolds, nano-delivery systems), aiming to provide theoretical basis and translational directions for optimizing SCI treatment and promoting in-depth development in this field.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs Regulation of Axon Sprouting in Peripheral Nerve Regeneration: A Systematic Review.","authors":"Elahe Khademi, Mohammad Reza Nourani, Ali Najafi","doi":"10.1007/s12035-026-06243-7","DOIUrl":"10.1007/s12035-026-06243-7","url":null,"abstract":"<p><p>Peripheral nerve injuries frequently result in long-term motor and sensory deficits, chronic pain, and incomplete functional recovery despite advances in surgical and rehabilitative approaches. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of gene expression that influence axonal sprouting and peripheral nerve regeneration. This systematic review synthesizes current evidence on the roles of key miRNAs, particularly miR-21, miR-133b, miR-124, and miR-30b, in modulating critical signaling pathways including PI3K/Akt/mTOR and Rho/ROCK. These miRNAs contribute to axonal outgrowth, Schwann cell responses, and the resolution of inflammation. Preclinical studies demonstrate that miRNA-loaded exosomes and other delivery platforms can enhance neurite outgrowth and functional recovery in models of sciatic nerve injury. Various delivery systems, including viral vectors, polymeric nanoparticles, hydrogels, and engineered exosomes, have been investigated for targeted miRNA administration. Nevertheless, challenges related to the complexity of miRNA regulatory networks, efficient and specific delivery, and scalable production remain significant barriers to clinical translation. Overall, miRNA-based strategies represent a promising avenue for improving outcomes after peripheral nerve injury, provided that current limitations in delivery and specificity can be effectively addressed.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Pattern Recognition Receptors (PRRs) in Spinal Cord Injury (SCI): A Comprehensive Review.","authors":"Hanieh Bayat, Mohammad Amini, Neda Ghaffari, Babak Ebrahimi, Davood Zarini, Gholamreza Hassanzadeh","doi":"10.1007/s12035-026-06240-w","DOIUrl":"10.1007/s12035-026-06240-w","url":null,"abstract":"<p><p>Spinal cord injury (SCI) is a severe disorder of the central nervous system (CNS) that leads to impairments in both motor and sensory functions. Immune system plays a critical role in SCI through various mechanisms conducted by neurons, glial cells, and their related secretions. Immune cells receive signals via their membrane and cytoplasmic receptors; among the most well-known of these are pattern recognition receptors (PRRs). This review examines structure, different subtypes, and the role of PRRs in SCI by summarizing animal studies. To identify relevant studies, a comprehensive literature search was carried out from inception to March 2026 using PubMed and Google Scholar databases. The search strategy combined Medical Subject Headings (MeSH) terms and keyword variations related to spinal cord injury, pattern recognition receptors, neuroinflammation, glial cells, immunomodulation and therapeutic interventions. Key findings include major families of PRRs, which contain Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), AIM2-like receptors (ALRs), and cyclic GMP-AMP synthase (cGAS), which are located on the cell surface, in endosomal compartments, or in the cytoplasm. Activation of PRRs can trigger signaling cascades that are involved in neuroinflammation, microglial polarity, gliosis, pyroptosis, excitotoxicity, demyelination, and locomotor function. Additionally, preclinical studies in SCI animal models represent PRRs as potential therapeutic targets, in which activators of TLR2 or suppressors of other types of PRRs could represent a promising avenue for SCI recovery. Further investigations are warranted to clarify the underlying mechanisms of PRRs and their immunomodulatory effects on SCI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HTR3A Receptor Signaling in Human Disease: From Bioelectrical Regulation to Therapeutic Targeting.","authors":"Ghasem Ahangari, Fatemeh Abedini, Shadi Ghaemi","doi":"10.1007/s12035-026-06246-4","DOIUrl":"10.1007/s12035-026-06246-4","url":null,"abstract":"<p><p>The 5-hydroxytryptamine receptor 3A (HTR3A) is the principal subunit of the 5-HT3 receptor and the only ionotropic member of the serotonin receptor family, mediating rapid cation influx and membrane depolarization following stimulation by serotonin. Beyond its established role in neurotransmission, growing evidence indicates that HTR3A functions as a critical regulator of bioelectrical signaling, influencing calcium homeostasis, neuronal excitability, immune responses, and diverse cellular processes implicated in human disease. This narrative review provides a comprehensive overview of the molecular structure, physiological functions, and pathological significance of HTR3A, with particular emphasis on its role in integrating bioelectrical mechanisms across multiple organ systems. Current evidence linking HTR3A dysregulation to cancer, neurological and psychiatric disorders, gastrointestinal diseases, inflammatory conditions, and pain is critically evaluated, highlighting shared electrophysiological pathways that may underlie these seemingly distinct pathologies. We further discuss the therapeutic potential of HTR3A-targeted interventions, including the repurposing of clinically approved 5-HT3 receptor antagonists, and examine emerging opportunities for biomarker development and precision medicine. Although substantial progress has been made in elucidating the biological functions of HTR3A, significant challenges remain regarding its context-dependent roles, mechanistic complexity, and clinical translation. By integrating molecular, electrophysiological, and translational evidence, this review proposes a unifying framework in which HTR3A-mediated bioelectrical signaling represents a common mechanistic axis linking diverse human diseases, thereby providing new perspectives for future mechanistic investigations and targeted therapeutic strategies.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epiregulin Mitigates Type 2 Diabetes-associated Cognitive Dysfunction by Inhibiting Hippocampal Neuronal Ferroptosis via the Nrf2 Pathway.","authors":"Zhen Zhang, Chujie Chen, Zhaolin Chen, Yunchong Guo, Ying Feng, Dan Liu, Yaqing Wen, Peng Yun, Xiahong Lin","doi":"10.1007/s12035-026-06226-8","DOIUrl":"10.1007/s12035-026-06226-8","url":null,"abstract":"<p><p>To investigate whether epiregulin (EREG) mitigates type 2 diabetes-associated cognitive dysfunction (T2DM-ACD) by inhibiting hippocampal ferroptosis via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. T2DM mice received EREG or vehicle for 4 weeks. Cognitive function was assessed by Morris water maze. Hippocampal neuronal damage was evaluated by Nissl staining, and ferroptosis-related protein expression was assessed by immunofluorescence. Transcriptomic profiling was performed by RNA sequencing in HT22 cells under control, high-glucose, and EREG-treated conditions. HT22 hippocampal neurons were exposed to high glucose with or without EREG, and the Nrf2 inhibitor ML385 was added to verify pathway dependency. Mitochondrial ultrastructure was observed by transmission electron microscopy. Ferroptosis-related indices, including lipid reactive oxygen species (lipid ROS), malondialdehyde (MDA), glutathione (GSH), and intracellular ferrous iron (Fe²⁺) levels, were measured by flow cytometry and biochemical assays. The expression of Nrf2 pathway proteins, including Nrf2, solute carrier family 7 member 11 (SLC7A11), and GPX4, was analyzed by western blotting. In vivo, EREG ameliorated cognitive deficits and hippocampal neuronal damage in T2DM mice, restoring glutathione peroxidase 4 (GPX4) and suppressing cyclooxygenase-2 (COX2) expression. In vitro, EREG reversed high glucose-induced transcriptomic alterations, enriched antioxidant pathways, preserved mitochondrial integrity, reduced lipid ROS, MDA, and Fe²⁺ accumulation, and restored GSH levels. Mechanistically, EREG activated the Nrf2-SLC7A11-GPX4 signaling axis, and these effects were reversed by the Nrf2 inhibitor ML385. EREG protects against T2DM-ACD by inhibiting hippocampal ferroptosis in an Nrf2-dependent manner, representing a potential therapeutic candidate.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Intensity Interval Training Ameliorates High-Fat Diet-Induced Cognitive Impairment and Is Associated with Altered Adipokine Signaling in the Olfactory Bulb and Hippocampus.","authors":"Farzaneh Zeynali, Maryam Delfan, Mazaher Rahimpour, Khadija Ayed, Ismail Laher, Anthony C Hackney, Hassane Zouhal","doi":"10.1007/s12035-026-06242-8","DOIUrl":"10.1007/s12035-026-06242-8","url":null,"abstract":"<p><p>High-fat diets have become increasingly common, but their negative impact on cognitive health is of growing concern. Such diets are associated with deficits in spatial learning and memory, particularly impacting brain regions such as the olfactory bulb (OB) and hippocampus (HPC). We investigated the benefits of high-intensity interval training (HIIT) on high-fat diet-induced deficits in spatial learning and memory, focusing on the OB and HPC. Eighteen C57BL/6 mice were divided into three groups (n = 6 per group): (1) normal control (NC), (2) high-fat diet (HFD), and (3) HFD with HIIT training (HFD + HIIT). The HFD groups were fed a 60% HFD for 12 weeks, after which mice in the HFD + HIIT group underwent 8 weeks of HIIT (5 days per week). The Barnes maze test was conducted during the last week of HIIT, and tissue levels of leptin, adiponectin, and their receptors in the OB and HPC were then measured. Consumption of a HFD decreased cell counts (OB: p = 0.001; HPC: p = 0.01), adiponectin levels (OB: p = 0.0002; HPC: p = 0.018), and adiponectin receptors in both the OB and HPC (OB: p = 0.0003; HPC: p = 0.052). In contrast, a HFD increased leptin levels and its receptors in both the OB and HPC (OB: p < 0.0001, p < 0.0001; HPC: p = 0.0003, p = 0.003, respectively), resulting in detrimental effects on spatial learning and memory. These effects of HFD were partially reversed by HIIT (p < 0.05). These findings identify the OB as a previously underexplored brain region that exhibits adipokine-related adaptations following HIIT and is associated with improvements in spatial memory in HFD-fed mice. Further mechanistic studies are needed to determine whether OB signaling directly contributes to these cognitive effects.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Timing at Mitochondrial Redox-Autophagy-Mitophagy Checkpoints in Age-Related Hearing Loss.","authors":"Shu Zhang, Qiang Zhang, Nan Sun, Jiye Zhong, Gang Liu, Chao Cai","doi":"10.1007/s12035-026-06234-8","DOIUrl":"https://doi.org/10.1007/s12035-026-06234-8","url":null,"abstract":"<p><p>Age-related hearing loss (ARHL) is common, disabling, and still managed largely with compensatory devices rather than mechanism-modifying therapy. The major weakness in the current translational pipeline is not the absence of candidate pathways, but the lack of a timing framework that links cochlear phenotype, mitochondrial injury state, and intervention intensity. This revised Review therefore focuses on a staged mitochondrial redox-quality-control model. We argue that ARHL emerges when high-energy cochlear compartments-outer and inner hair cells, spiral ganglion neurons, and the lateral wall/stria vascularis-cross a threshold at which mitochondrial reactive oxygen species (ROS), impaired mitochondrial DNA and transfer RNA integrity, lysosomal insufficiency, and incomplete mitophagy reinforce each other. Three checkpoints are emphasized because they are mechanistically actionable and experimentally measurable: NAD⁺-SIRT3-dependent mitochondrial deacetylation and antioxidant stabilization, NRF2-dependent redox and detoxification buffering, and PINK1-Parkin-dependent selective mitophagy. We also expand the sidewall perspective, highlighting that strial and spiral ligament redox instability can reduce endocochlear-potential reserve and modify the apparent sensory-neural phenotype. A practical therapeutic sequence is proposed: early substrate reinforcement through NAD⁺-SIRT3 and NRF2; mid-stage restoration of autophagy-lysosome competence; and selective mitophagy enhancement only when flux, not merely marker accumulation, is demonstrably limiting. Finally, we define a biomarker and detection framework that distinguishes cochlear tissue endpoints from blood or perilymph proxies and separates mouse proof-of-mechanism from human trial stratification. This approach clarifies which evidence is sufficient for prevention studies, which remains missing, and how future ARHL trials can be aligned with mechanism and timing.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pterostilbene Attenuates Neuronal Ferroptosis After Traumatic Brain Injury: Involvement of the SIRT1/PGC-1α/NRF2 Signaling Pathway.","authors":"Jianliang Li, Xuesong Zhang, Ning Wang, Hongbo Cheng, Shimei Dai, Zhuang Jing, Xuerui He, Yu Gong, Yinbo Long, Jiegang Yu, Jian Song, Baohai Yu, Yang Wu, Yaqing An","doi":"10.1007/s12035-026-06222-y","DOIUrl":"10.1007/s12035-026-06222-y","url":null,"abstract":"<p><p>Ferroptosis is increasingly recognized as a key driver of neurological damage following traumatic brain injury (TBI). Pterostilbene (PTE), a natural dimethylated analog of resveratrol, possesses superior blood-brain barrier (BBB) permeability and potent antioxidant properties, suggesting therapeutic potential for neurological disorders. However, the specific role and underlying mechanisms of PTE in TBI-induced ferroptosis remain largely unexplored. In the present study, we demonstrate that PTE treatment significantly ameliorates TBI pathology, as evidenced by reduced lesion volume, attenuated neuronal loss, and improved neurological recovery. We further confirm that PTE suppresses ferroptosis in a GPX4-dependent manner, a finding validated across both in vivo TBI mouse models and in vitro erastin-induced HT22 cell models. Mechanistically, PTE enhances resistance to ferroptosis through the engagement of the SIRT1/PGC-1α signaling pathway. Specifically, we found that PGC-1α is closely associated with the recruitment of nuclear NRF2 to the Gpx4 promoter region, co-activating its transcription and subsequently inhibiting ferroptosis. Clinical data further support these findings, revealing that higher expression levels of SIRT1 and PGC-1α correlate with favorable long-term outcomes in TBI patients, as assessed by the Glasgow Outcome Scale (GOS). Collectively, our results provide novel insights into the neuroprotective mechanisms of PTE and support its clinical potential in mitigating neuronal ferroptosis after TBI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}