Prabhakar Tiwari, Rekha Dwivedi, Meenakshi Kaushik, Manjari Tripathi, Rima Dada
{"title":"Genetics and Epigenetics of Alzheimer's Disease: Understanding Pathogenesis and Exploring Therapeutic Potential.","authors":"Prabhakar Tiwari, Rekha Dwivedi, Meenakshi Kaushik, Manjari Tripathi, Rima Dada","doi":"10.1007/s12031-025-02363-2","DOIUrl":"https://doi.org/10.1007/s12031-025-02363-2","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder that affects millions of individuals globally. Despite extensive research efforts, effective treatments for AD remain elusive. AD pathogenesis is driven by a combination of genetic, epigenetic, and environmental factors. However, challenges persist in AD genetic and epigenetic research, including the need for larger and more diverse cohorts, the integration of multi-omic data, and the development of advanced computational and experimental tools. A comprehensive understanding of these factors is crucial for the development of effective treatments and ultimately a cure for this debilitating condition. In this review, we summarize key regulatory pathways involved in AD pathogenesis, emphasizing genetic factors such as the apolipoprotein E (APOE) gene and high-impact genetic mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1). We also explore significant epigenetic regulators, including DNA methylation, histone deacetylases (HDACs), and microRNAs (miRNAs), which modulate gene expression and contribute to disease progression. Furthermore, we discuss the interplay between genetic and epigenetic factors, highlighting their combined impact on β-amyloid deposition, tau pathology, neuroinflammation, and synaptic dysfunction. Finally, we examine the potential of epigenetic modifications as promising therapeutic targets for AD, due to their reversible nature, and propose future research directions to address current knowledge gaps. This review offers an updated perspective on AD genetics and epigenetics, providing insights into novel avenues for therapeutic intervention.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":"72"},"PeriodicalIF":2.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S Cilem Kizilpinar, F Bahar Atak-Akkus, Ozlem Dogan, Burcin Colak, M Cigdem Aydemir
{"title":"Exploring the Sensitivity of Peripheral ADA Levels Measurement in Establishing Psychosis Susceptibility.","authors":"S Cilem Kizilpinar, F Bahar Atak-Akkus, Ozlem Dogan, Burcin Colak, M Cigdem Aydemir","doi":"10.1007/s12031-025-02362-3","DOIUrl":"https://doi.org/10.1007/s12031-025-02362-3","url":null,"abstract":"<p><p>Studies on the relationship between the adenosinergic system and schizophrenia have been released, but none has explored the relationship between adenosine deaminase and psychosis risk. Our primary objective is to investigate the sensitivity and specificity of peripheral adenosine deaminase enzyme levels regarding susceptibility to psychosis. In this cross-sectional case-control study, the serum levels of adenosine deaminase were compared among patients with schizophrenia, first-degree relatives of schizophrenia patients, and healthy controls. The patient and relative groups were classified as high-risk groups and healthy controls as low-risk groups. A binary logistic regression analysis was conducted to determine whether serum ADA levels can distinguish the low-risk group from the high-risk group. Healthy controls had higher serum ADA levels than the patient and relative groups (p = 0.019; p = 0.027). There was no statistically significant difference between patients and relatives (p = 0.998). Binary logistic regression analysis showed that serum ADA levels were 62.2% accurate in predicting psychosis risk, with a sensitivity of 82%. The results showed that serum ADA levels were significantly different between individuals at relatively low genetic risk (healthy controls) for schizophrenia and those at relatively high genetic risk (patients and relatives). According to the risk model based on serum ADA level, measuring serum ADA level may help distinguish genetically high-risk individuals from genetically low-risk individuals.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":"71"},"PeriodicalIF":2.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alejandrina Funes, Abraham I. Ramirez, Cintia N. Konjuh, Silvana B. Rosso, Santiago Cuesta, Alejandra M. Pacchioni
{"title":"Effects of Adolescent Social Isolation on PFC’s β-Catenin Levels and Anxiety-Like Behaviors in Male and Female Rats: Study of the Role of Dopaminergic D2 Receptors","authors":"Alejandrina Funes, Abraham I. Ramirez, Cintia N. Konjuh, Silvana B. Rosso, Santiago Cuesta, Alejandra M. Pacchioni","doi":"10.1007/s12031-025-02341-8","DOIUrl":"10.1007/s12031-025-02341-8","url":null,"abstract":"<div><p>Adolescence is a key period of development when major cognitive and neurobiological changes occur. Results from our lab showed that 5 days of social isolation in adolescent rats led to molecular changes in the Wnt/β-catenin pathway and to higher cocaine responses during adulthood. We assessed whether 5 days of social isolation (SI) during adolescence would impact on β-catenin levels in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) as well as on anxiety-like behaviors in a sex- and time-dependent manner. We also investigated the role of dopaminergic neurotransmission on that impact, by using repeated administration of a D2 antagonist. Male and female Wistar rats were socially isolated between postnatal day (PND)30 to 35 or kept in their home cages (non-isolated), while they were treated with sulpiride (100 mg/kg, <i>ip</i>) or vehicle. Anxiety-like behaviors and exploratory activity were estimated by the open field test at 24 h (PND36) or 9 days (PND44) after isolation. Then, they were euthanized at PND36 or PND45, and β-catenin levels were analyzed by Western blot in PFC and NAcc. Our findings show that a brief SI during adolescence leads to a long-term impact on both β-catenin levels (10 days, PND45) and anxiety-like behaviors (9 days, PND44) with a significant increase and decrease, respectively, in female rats. In contrast, male rats show a rapid decrease in β-catenin levels in the PFC with no changes in anxiety-like behaviors (24 h, PND36). These suggest that adolescent SI induces mostly long-term changes in female while short term changes in male rats. Moreover, these changes seem to be modulated by dopaminergic neurotransmission since a sulpiride treatment during isolation prevented them.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ayad Babaee, Thea Overgaard Wichmann, Mikkel M. Rasmussen, Ole Brink, Dorte Aalund Olsen, Lars C. Borris, Maj Lesbo, Rikke Wehner Rasmussen, Carlos Salomon, Aase Handberg, Maiken Mellergaard, Claus V. B. Hviid
{"title":"Extracellular Vesicle Glial Fibrillary Acidic Protein as a Circulating Biomarker of Traumatic Brain Injury Severity","authors":"Ayad Babaee, Thea Overgaard Wichmann, Mikkel M. Rasmussen, Ole Brink, Dorte Aalund Olsen, Lars C. Borris, Maj Lesbo, Rikke Wehner Rasmussen, Carlos Salomon, Aase Handberg, Maiken Mellergaard, Claus V. B. Hviid","doi":"10.1007/s12031-025-02360-5","DOIUrl":"10.1007/s12031-025-02360-5","url":null,"abstract":"<div><p>Traumatic brain injury (TBI) remains a major global health challenge with a need for improved diagnostic and prognostic biomarkers. This study aimed to evaluate the biomarker potential of extracellular vesicle (EV)-encapsulated glial fibrillary acidic protein (EV-GFAP), neurofilament light chain (EV-NfL), total tau (EV-T-Tau), and ubiquitin carboxy-terminal hydrolase L1 (EV-UCH-L1) in TBI. A cohort of 93 trauma patients (75 with TBI and 18 without TBI) was analyzed. Patients were sampled on admission, as well as 15 and 72 h post-injury. Following initial method validation, EVs were isolated from plasma using size exclusion chromatography (SEC), and plasma levels and EV cargo levels of biomarkers were measured using an ultra-sensitive Single Molecule Array. EV-GFAP levels were significantly elevated in TBI patients compared to non-TBI trauma patients at admission and 15 h. A positive head CT was associated with 2.85 (95% CI: 1.18–6.91) fold increased EV-GFAP, whereas EV-NfL, EV-T-Tau, and EV-UCH-L1 levels were not affected. None of the tested EV biomarkers were associated with 1-year mortality or 6–12 months’ functional outcome. Plasma-GFAP levels increased 3.4 (95% CI: 1.72–6.70) fold with a positive head CT but were not associated with outcomes. EV-GFAP shows potential as an early biomarker of TBI, but plasma-GFAP remains a practical and reliable alternative. Future studies should explore the potential complementary roles of EV-based biomarkers on alternative aspects of TBI pathophysiology and prediction of long-term outcomes. Studies should refine methods to enhance reproducibility and clinical applicability.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-025-02360-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144125584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fereshteh Golab, Pooya Hajimirzaei, Sam Zarbakhsh, Samira Zolfaghari, Parisa Hayat, Mohammad Taghi Joghataei, Fatemeh Bakhtiarzadeh, Nooshin Ahmadirad
{"title":"Interplay of Neuroinflammation and Epilepsy in Glioblastoma Multiforme: Mechanisms and Therapeutic Implications","authors":"Fereshteh Golab, Pooya Hajimirzaei, Sam Zarbakhsh, Samira Zolfaghari, Parisa Hayat, Mohammad Taghi Joghataei, Fatemeh Bakhtiarzadeh, Nooshin Ahmadirad","doi":"10.1007/s12031-025-02335-6","DOIUrl":"10.1007/s12031-025-02335-6","url":null,"abstract":"<div><p>Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer in adults and is characterized by poor prognosis and a high incidence of seizures due to tumor-induced alterations in cerebral physiology. This review explores the complex interactions between GBM-induced neuroinflammation and epilepsy, emphasizing the mechanisms of epileptogenesis influenced by blood–brain barrier dysfunction, ion homeostasis, and neurotransmitter dynamics. We discuss the roles of pro-inflammatory mediators such as interleukin-1β and tumor necrosis factor-alpha in exacerbating excitatory synaptic activity while inhibiting inhibitory signaling, thus creating a milieu conducive to seizure activity. Furthermore, we evaluated the efficacy of current anti-seizure medications and emerging therapeutic strategies, including the reprogramming of tumor-associated macrophages, in managing GBM-related epilepsy and tumor growth. This study aimed to elucidate the critical pathways connecting GBM and epilepsy, thereby advancing our understanding of potential interventional approaches to improve patient outcomes.\u0000</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"From Genetics to Function: the Role of ABCA12 in Autism Neurobiology","authors":"Akansha Pal, Falguni Goel, Vipin Kumar Garg","doi":"10.1007/s12031-025-02357-0","DOIUrl":"10.1007/s12031-025-02357-0","url":null,"abstract":"<div><p>ASD is a complex neurodevelopmental disorder with genetic, environmental, and molecular roots. Among the thousands of genes that have been associated with ASD, one critical factor has emerged as ABCA12, which plays an important role in lipid transport and metabolism. Traditionally, it has been related to skin disorders but has only recently been implicated in broader brain development and function. Some of the implicated effects include dysregulated lipid homeostasis, neuroinflammation, oxidative stress, and abnormalities in synaptic when the ABCA12 system is dysregulated. All the above processes are related to pathology in ASD. In this review, the emerging function of ABCA12 in autism neurobiology has been discussed; the core base is derived from in vivo models and preclinical studies. In vivo models such as mice and zebrafish that, in the previous studies had earlier shown impairments of ABCA12 which results in social deficiency behaviors but also perform repetitive actions. Based on the effects of the gene on molecular pathways, including neuronal signalling and membrane integrity, and identifying therapeutic approaches targeting ABCA12 or its downstream effects, preclinical studies have contributed to the integration of genetic, functional, and therapeutic perspectives for understanding the contribution of ABCA12 to ASD. These findings may unlock further investigations geared toward unravelling how lipid metabolism intricately influences neurodevelopment with regards to interventions available for use in ASD.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143949522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mahinaz A. Mashhour, Ibrahim Youssef, Manal Abdel Wahed, Mai S. Mabrouk
{"title":"The Intersection of Genetics and Neuroimaging: A Systematic Review of Imaging Genetics in Neurological Disease for Personalized Treatment","authors":"Mahinaz A. Mashhour, Ibrahim Youssef, Manal Abdel Wahed, Mai S. Mabrouk","doi":"10.1007/s12031-025-02350-7","DOIUrl":"10.1007/s12031-025-02350-7","url":null,"abstract":"<div><p>Imaging genetics is one of the important keys to precision medicine that leads to personalized treatment based on a patient’s genetics, phenotype, or psychosocial characteristics. It deepens the understanding of the mechanisms through which genetic variations contribute to neurological and psychiatric disorders. This systematic review overviews the methods and applications of imaging genetics in the context of neurological diseases, mentioning its potential role in personalized medicine. Following PRISMA guidelines, this review systematically analyzes 28 studies integrating genetic and neuroimaging data to explore disease mechanisms and their implications for precision medicine. Selected research included multiple neurological disorders, including frontotemporal dementia, Alzheimer’s disease, bipolar disorder, schizophrenia, Parkinson’s disease, and others. Voxel-based morphometry was the most common imaging technique, while frequently examined genetic variants included APOE, C9orf72, MAPT, GRN, COMT, and BDNF. Associations between these variants and regional gray matter loss (e.g., frontal, temporal, or subcortical regions) suggest that genetic risk factors play a key role in disease pathophysiology. Integrating genetic and neuroimaging analyses enhances our understanding of disease mechanisms and supports advancements in precision medicine.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-025-02350-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jinan Han, Ying Xu, Yan Zhou, Ning Zhu, Jiazhen Gao, Li Huang
{"title":"Therapeutic Hypothermia and Recombinant Erythropoietin Mitigate Brain Microvascular Endothelial Cell Dysfunction via Modulating the Pentose Phosphate Pathway","authors":"Jinan Han, Ying Xu, Yan Zhou, Ning Zhu, Jiazhen Gao, Li Huang","doi":"10.1007/s12031-025-02356-1","DOIUrl":"10.1007/s12031-025-02356-1","url":null,"abstract":"<div><p>Neonatal brains are particularly vulnerable to oxidative stress, making the pentose phosphate pathway (PPP) pivotal in damage limitation. This study aimed to confirm the mechanism of erythropoietin combined with therapeutic hypothermia (TH) in hypoxic-ischemic brain damage (HIBD). Neonatal HIBD rat models were employed and the impacts of erythropoietin and TH on behavior, cerebral infarction, pathology, and microvascular were evaluated. Following that, the assessments of inflammation, oxidative stress, apoptosis, and the level of glucose-6-phosphate dehydrogenase (G6PD, rate-limiting enzyme in the PPP) proceeded. Human brain microvascular endothelial cells (HBMECs) underwent oxygen–glucose deprivation (OGD) and were treated with TH and G6PD inhibitor RRx-001. The impacts of the G6PD inhibitor on HBMEC function and barrier were evaluated. Simultaneous administration of TH and EPO reduced pathological damage and attenuated microvascular loss. In addition, this combination therapy had anti-inflammatory, antioxidant, and anti-apoptotic properties, and enhanced G6PD activity, both in vivo and in vitro. Inhibition of G6PD disrupted the protective effects of TH and EPO on the patency of the PPP and the function of HBMECs, and barrier integrity was further broken. This study reveals that the combination of TH and EPO mitigates microvascular endothelial cell dysfunction via partially modulating the PPP, thus preserving barrier integrity.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143925641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wisam H. Hoidy, Mohammed H. Al-Saadi, Simon Clegg, Doaa H. Chyad
{"title":"Association of Alzheimer’s-Related Gene Variants with Autism Spectrum Disorder: A Case–Control Study in an Iraqi Cohort","authors":"Wisam H. Hoidy, Mohammed H. Al-Saadi, Simon Clegg, Doaa H. Chyad","doi":"10.1007/s12031-025-02359-y","DOIUrl":"10.1007/s12031-025-02359-y","url":null,"abstract":"<div><p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder that manifests as difficulties in social communication and the presence of restricted and repetitive behaviors. The etiology remains obscure, although there is increasing evidence of shared neurodevelopmental and neurodegenerative disorder pathways. This study aimed to determine whether gene variants previously linked to Alzheimer’s disease (AD) have a role in ASD susceptibility. Within a case–control framework, we studied a sample of 270 Iraqi children, 135 with ASD and 135 age-matched controls aged 6–12 years. T-ARMS PCR was used to determine the genotypes of five selected polymorphisms NECTIN2 (rs6859), CR1 (rs670173), CLU (rs7982), ABCA7 (rs3764650), and BIN1 (rs744373) that have been associated with AD. The polymorphism genotype and allele frequencies were analyzed using the chi-square test, and odds ratio analysis with 95% confidence intervals was conducted. Age and sex-stratified analyses in addition to biochemical profiling were also conducted. Significant associations with ASD were found for three polymorphisms: CR1 rs670173 (<i>p</i> = 0.007), CLU rs7982 (<i>p</i> = 0.010), and BIN1 rs744373 (<i>p</i> = 0.013). The male-to-female effect ratio was stronger than the female-to-male. Interestingly, younger boys aged 6 to 9 years demonstrated the most pronounced effect of CLU rs7982 (OR = 1.92, 95% CI: 1.25–2.94, <i>p</i> = 0.003). NECTIN2 rs6859 (<i>p</i> = 0.543) and ABCA7 rs3764650 (<i>p</i> = 0.102) did not yield significant associations. Biochemical parameters showed no significant differences among the groups. Our results imply that some AD-associated gene variants, especially those related to neuroinflammation and synaptic activity, could elevate the risk for ASD. This reinforces the notion of shared genetic risk factors between neurodevelopmental and neurodegenerative disorders, likely involving common mechanisms for the formation and maintenance of neural circuits.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Electroacupuncture Inhibits Ferroptosis by Modulating Iron Metabolism and Oxidative Stress to Alleviate Cerebral Ischemia–Reperfusion Injury","authors":"Yaoyao Liu, Qi Wang, Ziwen Hou, Ying Gao, Peng Li","doi":"10.1007/s12031-025-02355-2","DOIUrl":"10.1007/s12031-025-02355-2","url":null,"abstract":"<div><p>Ischemic stroke (IS) is one of the leading causes of mortality and long-term disability worldwide. Electroacupuncture (EA) is commonly used in the treatment of IS, meaning that may reduce cerebral ischemia–reperfusion injury (CIRI). The middle cerebral artery occlusion/reperfusion (MCAO/R) rat models were created by the modified Zea Longa suture method. EA treatment was performed for 7 consecutive days at the acupoints Neiguan (PC6), Shuigou (GV26), and Sanyinjiao (SP6). The neurological function was assessed using the Zausinger six-point neurological deficiency score. The cerebral infarct volume was detected by 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Hematoxylin and eosin (HE) staining was employed to observe the pathological changes in brain tissues. Prussian blue staining was employed to investigate iron deposition within the brain tissues. Transmission electron microscopy (TEM) was utilized to examine the morphological characteristics of mitochondria. Simultaneously, flow cytometry was utilized to detect the fluorescence intensity of reactive oxygen species (ROS). Assay kits were employed to measure the levels of Fe<sup>2+</sup> and glutathione (GSH). Additionally, western blot (WB) and real-time quantitative polymerase chain reaction (RT-qPCR) assays were performed to evaluate the expression levels of proteins associated with ferroptosis. Compared with the MCAO/R group, both the MCAO/R + EA and MCAO/R + DFO groups exhibited significant improvements in neurological function following cerebral ischemia–reperfusion (CIR), attenuated the pathological brain tissue injury, and reduced the cerebral infarct volume and iron deposition in brain tissue. Furthermore, both the MCAO/R + EA and MCAO/R + DFO groups displayed a marked reduction in mitochondrial injury. There was a substantial decrease in Fe<sup>2+</sup> and ROS levels, accompanied by a notable increase in GSH level and glutathione peroxidase 4 (GPX4) activity. Compared with the MCAO/R group, the levels of ferroportin1 (FPN1) protein and mRNA expression were significantly increased in the MCAO/R + EA and MCAO/R + DFO groups, and the expression levels of transferrin (TF), transferrin receptor 1 (TFR1), divalent metal transporter 1 (DMT1) protein and mRNA, as well as ferritin (FER) protein, were significantly decreased. EA inhibits ferroptosis by modulating iron metabolism and oxidative stress to alleviate CIRI, exerting neuroprotective effects.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"75 2","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-025-02355-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}