Most preclinical Parkinson's disease (PD) models use neurotoxic agents to cause rapid dopaminergic neuron degeneration, mimicking the late stage of PD. That creates a gap in understanding early-stage pathophysiology, critical for neuroprotective therapies and early diagnosis. To replicate the prodromal stage of PD, it is pivotal that preclinical study models promote a slow and selective death of dopaminergic neurons, triggering degenerative processes and early symptoms. In this context, we investigated behavioral and neuronal changes using a model of unilateral aminochrome injection (6 nmol/6 μL) in the striatum of adult male Wistar rats (CEUA-ICS, Protocol 3006070223), focusing on subtle changes representative of the early stages of PD. On the fourteenth day after the stereotaxic injection, we observed behavioral impairments marked by a reduction of frequency of entries, time spent and distance traveled in the central quadrants in the open field test, reduction of frequency of rearing and grooming in the open field, as well as an increase in the rate of motor asymmetry in the cylinder test. In addition, we observed a decrease in the transition of animals through the elevated plus maze, with a reduction in the number of entries into the open arm. Immunohistochemical analyses indicated that aminochrome induces cytotoxicity for tyrosine hydroxylase-positive (TH) cells and induces astrogliosis and microgliosis. Our findings show that striatal injection of aminochrome induces a reduction in the density of TH fibers in the striatum, a slight reduction in the number of dopaminergic neurons in the caudal and medial regions of the nigra pars compacta (SNpc), and subtle motor deficits typical of an early stage of PD. Here, we provided evidence that aminochrome can induce a rodent model of the prodromal stages of PD.

The blood-brain barrier is an anatomical structure responsible for controlling the flux of nutrients, metabolites, and xenobiotics into and out of the brain. This fundamental function is carried out through the coordinated action of specific ion channels and membrane transporters belonging to the SLC and ABC superfamilies. Indeed, membrane transporter expression in the BBB is less redundant than in other parts of the body. Therefore, any alteration to one of these proteins may pose a threat to the brain. The fifth member of the SLC7 family, which is expressed at the BBB has been the subject of much research over the years. SLC7A5, also known as LAT1, is a plasma membrane transporter of essential amino acids, whose role in brain development is well recognised. The protein is expressed in the membranes of BBB vessels, neurons, and microglia, creating a connection between different areas of the human brain. LAT1 received significant attention in the context of brain tumor treatment, particularly for glioblastoma multiforme, a malignancy with a poor prognosis characterised by fatal relapses. Since several drugs are also substrates of LAT1, its expression at the BBB could be exploited to deliver drugs that target brain diseases. This review describes the functional, structural, and regulatory features of LAT1, focusing on pharmacology in the context of brain homeostasis.

Trigeminal neuralgia (TN) is the most common type of cranial neuralgia. Currently, there remains a significant gap in the availability of effective and safe treatment options in clinical practice. Transdifferentiation of proliferating activated astrocytes into inhibitory neurons is a potential therapeutic strategy for central nervous system diseases. GABAergic neurons are one of the most type of prevalent inhibitory neurons. This study aims to reprogram proliferating astrocytes in the spinal trigeminal subnucleus caudalis (SpVc) into GABAergic neurons, could improve neuronal excitation-inhibition balance, alleviate pain, which serve as a potential treatment for trigeminal neuralgia. A chronic constriction injury of the distal infraorbital nerve (CCI-dION) was induced in the infraorbital branch of the trigeminal nerve to create a rat model of TN. Adeno-associated viruses were used to overexpress transcription factors Sox2 and Mash1 in astrocytes. The changes in astrocytes and GABAergic neurons in the SpVc region were detected by immunofluorescence, Western blotting, qPCR, and electron microscopy. The mechanical pain threshold testing was used to assess rat TN. In the SpVc region of CCI-dION rats, astrocytes showed proliferation and activation, and the number of GABAergic neurons decreased significantly. Overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which - improved the mechanical pain threshold in CCI-dION rats. Furthermore, fluorocitrate-mediated astrocyte deactivation abolished both the neuronal reprogramming and the analgesic effects, underscoring the essential role of astrocytes in this process. These findings suggest that overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which significantly improved the mechanical pain threshold in CCI-dION rats. Thus, this approach has the potential to provide a new treatment for TN.

Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a component of the wave regulatory complex (WRC), one of the most important players in regulating cellular actin dynamics. Interestingly, the CYFIP2 transcript undergoes RNA editing, an epitranscriptomic modification catalyzed by ADAR enzymes, which leads to adenosine (A) to inosine (I) deamination. CYFIP2 editing in the coding sequence results in a K/E substitution at amino acid 320. The functional meaning of this regulation is still unknown. In this study, we aimed to investigate the potential implications of CYFIP2 RNA editing related to actin dynamics during cell differentiation, axon development and synaptogenesis in neural cells. We generated SH-SY5Y neuroblastoma cell lines in which the CYFIP2 gene has been functionally inactivated via CRISPR-Cas9 technology. CYFIP2 KO cells exhibited profound actin filament disorganization and loss of the ability to differentiate into a neuron-like phenotype. The overexpression of both the unedited (K) and edited (E) CYFIP2 isoforms restored normal abilities. Finally, we used primary neuronal cultures in which endogenous CYFIP2 was knocked down via short hairpin RNA (shRNA) technology and CYFIP2 editing variants were overexpressed. While CYFIP2-KD cells presented a decrease in axon development and spine frequency, CYFIP2-E variants increased the number of axon branches, total axon length and dendritic spine frequency compared with both CYFIP2-KD cells and CYFIP-K variants. Overall, our work reveals for the first time the functional significance of the CYFIP2 K/E RNA editing process in regulating the spread of neuronal axons during the initial stages of in vitro development and spinogenesis.

Gliomas exploit various molecular pathways to promote their survival, proliferation, and invasion. Recent studies reveal the complex neuron-glioma interaction and BDNF plays a major role in this interaction. However, it's unclear whether and how the BDNF-mediated cross-talk between neurons and gliomas is regulated. FSTL4 is reported to negatively regulate BDNF maturation. Here, we hypothesized that neuronal FSTL4 may negatively regulate BDNF-mediated neuron-glioma cross-talk. By using a combination of approaches like chemogenetic activation of primary neurons and CRISPR knockout/activation of endogenous FSTL4, we show that activated primary neurons support the proliferation of co-cultured glioma cells and neuronal BDNF secretion mediates this neuron-glioma interaction via activating TrkB in glioma cells. In addition, this process is negatively regulated by neuronal FSTL4 as its CRISPR KO in primary neurons further supports the proliferation of co-cultured glioma cells. Importantly, CRISPR activation of endogenous FSTL4 expression in primary neurons results in impaired ability to support co-cultured glioma cells, highlighting the therapeutic potential of activating endogenous FSTL4 for glioma treatment. Taken together, our study shows that the FSTL4/BDNF/TrkB axis plays an essential role in fine-tuning the neuron-glioma interaction and targeting this interplay with CRISPR tools may help to develop novel therapeutic strategies.

Therapeutic angiogenesis represents a pivotal yet underexplored avenue for functional recovery following cerebral ischemia. Although lipocalin-2 (LCN2) participates in neuropathological processes, its cell-type-specific regulation of post-ischemic vascular remodeling remains unknown. Here, we demonstrate that CRISPR/Cas9-mediated C8D1A astrocyte-like cells-specific LCN2 knockout significantly enhances vascular network formation in endothelial co-cultures under oxygen-glucose deprivation/reperfusion (OGD/R). Clinically, elevated LCN2 (GDS4521 dataset) correlates with poor stroke prognosis. Functional analyses revealed that AAV-shRNA-mediated LCN2 knockdown in photothrombotic stroke mice reduced infarct volume, attenuated peri-infarct neuronal loss, increased peri-infarct vascular density, and improved neurobehavioral outcomes at 7 days post-ischemia. Mechanistically, transcriptomic profiling identified hypoxia-inducible factor 1α (HIF-1α) as the master regulator of ischemia-induced angiogenesis. Molecular docking confirmed LCN2-HIF1α interaction. Furthermore, LCN2 ablation unleashes a HIF-1α/VEGF signaling cascade in C8D1A astrocyte-like cells, which activates endothelial phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) via paracrine mechanisms to drive functional revascularization. These findings not only redefine ischemic pathophysiology but also pioneers LCN2 inhibition as a translational strategy to overcome the limitations of current pro-angiogenic therapies in cerebrovascular disease.

Mild psychiatric conditions such as anxiety and depression, as well as severe disorders like schizophrenia and neurodegenerative diseases, are increasingly recognized as systemic inflammatory conditions. Platelets possess both hemostatic and immunomodulatory roles in these situations, with sharing key molecular pathways with the central nervous system, offering thus a valuable peripheral model for evaluating psychotropic drug effects. Platelet-activating factor (PAF), a potent thrombo-inflammatory mediator, has emerged as a potential link between the two systems, yet its involvement in drug responses remains understudied. This study systematically investigates the effects of psychotropic drugs (i.e. antidepressants, antipsychotics and anxiolytics), and neuroprotective (anti-Alzheimer's/Anti-Parkinson's) drugs on platelet aggregation, focusing on PAF-pathway in comparison to a control platelet agonist, ADP. Using ex vivo light transmission aggregometry, we determined IC values for each drug and analyzed the impact of selected drug combinations, in which the NSAID diclofenac was also included. Results revealed that most of the compounds assessed inhibited more effectively the PAF-induced aggregation of platelets compared to their effect on the ADP-pathway, with perphenazine showing the greatest anti-PAF potency. Several drug combinations, notably those including alprazolam and diclofenac, demonstrated significant synergistic effects. These findings suggest that commonly prescribed psychotropic drugs and medications for neurodegenerative disorders can influence platelet activity, mostly through the PAF-pathway, and that their interactions with NSAIDs may amplify their efficacy. Nevertheless, some drugs and their combinations induced lysis of platelets at much higher concentrations than their IC50 values, which stems safety concerns for their use.

Natural rewards such as food and drugs of abuse share the mesolimbic dopamine system, including the nucleus accumbens (NAcc), as a common neural pathway that influences appetite and addictive behavior. Ghrelin, an orexigenic hormone, acts synergistically with mesolimbic dopamine in this process. In the present study, we examined the effects of food restriction (FR) on plasma ghrelin levels and amphetamine (AMPH)-induced locomotor activity. Chronic FR (cFR) significantly enhanced AMPH-induced locomotor activity compared to normal feeding and acute FR (aFR), which was associated with increased plasma ghrelin and dopamine D1 receptor (D1R) expression levels in the NAcc. These effects were inhibited by either systemic or NAcc-specific administration of D1R or ghrelin receptor antagonists. Furthermore, rats under the aFR condition showed enhanced locomotor activity in response to intra-accumbal microinjection of the D1R agonist when pre-exposed to AMPH, whereas rats in the cFR condition showed these effects regardless of pre-exposures to either AMPH or saline. These results demonstrate that FR conditions interact with drugs of abuse via the accumbal ghrelin and D1R systems, thereby contributing to the expression of addictive behaviors. Notably, these findings suggest that dietary status should be considered during addiction treatment.

The metabolic processes within the brain are reflected in the cerebrospinal fluid (CSF). It is in close contact with the nervous system, which is both target and source of multiple steroids. The aim of our study was to develop and validate robust, sensitive LC-MS/MS methods with and without derivatization step for the analysis of unconjugated steroids from all major steroid classes in CSF. The validation of the method without derivatization was performed for ten C19- steroids (dehydroepiandrosterone (DHEA), 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, testosterone, epitestosterone, dihydrotestosterone, 11-hydroxytestosterone, 11-ketotestosterone and androstenedione), ten C21- steroids (cortisol, 11-deoxycortisol, 21-deoxycortisol, cortisone, corticosterone, 11-deoxycorticosterone, pregnenolone, progesterone, 17-hydroxyprogesterone, aldosterone) and three C18- steroids (estrone, estradiol, estriol). The method with derivatization is validated for determination of eleven C19- steroids (testosterone, 11-ketodihydrotestosterone, 11-hydroxytestosterone, DHEA, 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, androstenedione, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone) and six C21- steroids (cortisol, cortisone, corticosterone, pregnenolone, 17-hydroxypregnenolone, progesterone) in CSF. The method without derivatization is applicable for the determination of the majority of steroids in CSF, except for pregnenolone, 17-hydroxypregnenolone and DHEA, for which the derivatization method provides better sensitivity. When analyzing CSF samples of normal pressure hydrocephalus (NPH) patients, 11-ketodihydrotestosterone, epitestosterone, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone, 7-ketoDHEA and 21-deoxycortisol were found to be below the LLOQ, suggesting that their presence is very limited. 17-hydroxypregnenolone, and 11-deoxycortisol were quantified for the first time, their CSF levels in NPH subjects are presented. We also observed significantly increased CSF levels of testosterone and 17-hydroxyprogesterone in men compared to women, both with NPH.

Rapid restoration of cerebral blood flow through endovascular therapy is crucial for minimizing neuronal injury in ischemic stroke. This study characterized cellular and molecular alterations during the acute and subacute phases of distal middle cerebral artery occlusion (dMCAO) in mice using single-nucleus (snRNA-seq) and single-cell (scRNA-seq) RNA sequencing. C57BL/6 mice were assigned to control, sham, dMCAO 3-day, and dMCAO 14-day groups. snRNA-seq identified diverse cell populations, including neurons (glutamatergic and GABAergic), fibroblast-like cells, astrocytes, oligodendrocytes, microglia, endothelial cells, and pericytes. Microglia shifted from homeostatic (Siglech, P2ry12) to acute-phase (Lgals1, Top2a, Mki67) and disease-associated states, consistent with previous evidence confirming that our dataset captured stroke-related dynamics. snRNA-seq enabled efficient recovery and analysis of neurons, revealing stroke-induced cell state changes.; notably, glutamatergic neurons declined on day 3, while endothelial cells increased. Gene ontology analysis indicated neuronal death, autophagy, and cAMP biosynthesis pathways. Elevated Syngap1, Ikbkb, and Rock1 expression across glutamatergic subclusters suggested roles in cell death-related mechanisms and vulnerability to ischemic injury. Dissociation of SynGAP1 from PSD-95 after ischemia may enhance ERK1/2 phosphorylation, whereas ischemic preconditioning suppresses this dissociation and prevents ERK1/2 overactivation. Immunohistochemistry confirmed Syngap1 and cAMP response element-binding (CREB) pathway activation at 3 and 14 days post-ischemia, aligning with sequencing results. Suppressing CREB with pAAV-A-CREB reduced neuronal survival, underscoring its role in autophagy and neuroprotection. These findings provide mechanistic insight into stroke-induced molecular alterations and identify autophagy and cAMP pathways within the penumbra as promising therapeutic targets.

Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain. In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an App knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated App knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes. These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.

The unfolded protein response (UPR) is activated under different neuropathological conditions, such as brain ischemia, epilepsy, and neurodegeneration. We previously reported that a UPR transducer, activating transcription factor 6 (ATF6), and its downstream molecular chaperones in the endoplasmic reticulum (ER) have neuroprotective properties against excitotoxicity. In this study, we examined the temporal and spatial changes in the UPR activation after administration of an excitotoxic reagent, kainate (KA), into mice. RT-qPCR revealed enhanced expression of UPR genes, with peaks either on day 1 or day 3 after intrahippocampal KA injection. The status of the UPR was analyzed using ER stress-activated indicator (ERAI)-transgenic mice, in which the spliced form of XBP-1, downstream of the IRE1 branch of the UPR, can be monitored. ERAI-derived GFP signals were strongly observed in CA3 neurons and moderately observed in dentate gyrus neurons, but not in CA1 neurons, after KA injection. A small portion of the activated astrocytes was also positive for ERAI signals. Further studies revealed that ERAI signals were observed in both the soma and dendrites of neurons in regions with enhanced neuronal activity and resistance to KA toxicity. These results suggest that the UPR may be associated with the neuronal activity and survival after KA injection.

Glioblastoma multiforme (GBM), one of the most malignant brain cancers, responds poorly to chemotherapy and surgery. Transcription factor EB (TFEB) is markedly overexpressed in GBM cells. We investigated whether TFEB contributes to resistance to genotoxic stress and whether its inhibition promotes apoptosis of GBM cells and glioma stem cells (GSCs). Specifically, we examined whether combined treatment with etoposide and SAHA overcomes TFEB-mediated resistance and enhances apoptotic cell death. We examined the effects of etoposide, a topoisomerase II inhibitor, and SAHA, a histone deacetylase inhibitor, on TFEB expression and apoptotic signaling in human GBM cells and GSCs. To assess TFEB-mediated drug resistance, we measured cell viability, proliferation, and tumorsphere formation following single or combined treatments. Apoptotic signaling was analyzed by western blotting, MTT assays, and tumorsphere formation assays. Functional roles of TFEB were further investigated using overexpression and shRNA knockdown approaches. Treatment with etoposide induced apoptosis and reduced TFEB expression in GBM cells. Co-treatment with etoposide and SAHA synergistically increased cleaved PARP and phosphorylated H2AX levels, indicating enhanced apoptotic activity. In TFEB-overexpressing and knockdown GBM cells, apoptosis sensitivity varied according to TFEB expression levels. In GSCs, combination treatment significantly suppressed cell proliferation and tumorsphere formation, accompanied by reduced TFEB expression and oligomerization, and increased apoptosis. Our findings suggest that TFEB promotes the chemoresistance of GBM tumors and GSCs by suppressing apoptosis. Co-treatment with etoposide and SAHA inhibits TFEB activity and enhances apoptotic cell death, representing a promising therapeutic strategy for treating malignant brain tumors.

Post-traumatic stress disorder (PTSD) is a chronic psychological disorder that is induced by traumatic events. The pathophysiological mechanism of PTSD involves complex neurobiological processes. However, the underlying mechanism is not clear, leading to lack of effective therapeutic interventions.

Transgenerational epigenetic inheritance (TEI) refers to the transmission of phenotypic traits across multiple generations independent of changes in DNA sequence that are mediated by epigenetic mechanisms, including DNA methylation, histone modifications, chromatin morphology, and non-coding RNAs. This review focuses on manuscripts that report epigenetic mechanisms in the transgenerational inheritance of nervous system phenotypes in both mammalian and non-mammalian experimental models. Non-mammalian organisms such as C. elegans and Drosophila have been instrumental in disclosing TEI pathways comprising small RNA networks, histone-based modifications, and N6-methyladenine modifications that balance limited cytosine methylation. Authenticating TEI in mammals is complex due to extensive elimination of epigenetic factors and pathways essential for mitosis that do not participate in meiosis, germline development, and early embryogenesis, termed epigenetic "erasure" or "reprogramming". Specific epigenetic pathways that guide neural development, including DNA methylation at metastable epialleles and gamete-derived small RNAs, escape erasure, and have been linked to altered neurodevelopment and behavior in offspring. Together, these data indicate a role for epigenetic regulation in tuning neural circuits during neurodevelopment with enduring impacts on brain organization and behavior. This perspective situates neural TEI within a mechanistic framework that links early environmental exposures to long-lived neuronal circuit properties and behavioral outcomes. Accordingly, elucidating neural-specific TEI mechanisms alone and in combination will enhance our understanding of how ancestral environmental exposures shape neurological structures, functions, behaviors, and susceptibilities to disease across generations. The present review synthesizes current evidence, identifies key interpretative challenges, and details directions for future research in neural TEI.

In Alzheimer's disease, increased GSK3β activity drives tau phosphorylation and directly or indirectly triggers neuroinflammation, neuronal damage and cognitive decline. We previously developed a novel GSK3β inhibitor, ZLWH-60, which demonstrated inhibitory activity with an IC50 of 11.5 nM. Here, we comprehensively evaluated the therapeutic potential of ZLWH-60 in suppressing tau pathology and neuroinflammation using multiple chemically-induced AD models. Our results demonstrate that ZLWH-60 could reduce the phosphorylation of multiple tau epitopes by inhibiting the activity of GSK3β, thereby ameliorating cognitive impairments in OKA-induced mouse model. In the LPS-induced mouse model, ZLWH-60 also reduced the secretion of inflammatory factors in the brain, exerting a neuroprotective effect. Our data highlight that ZLWH-60, as a GSK3β inhibitor, has a powerful ability to reduce the phosphorylation of tau protein and shift the balance of the inflammatory response from pro-inflammatory to anti-inflammatory, demonstrating the potential for therapeutic use of this drug to control AD.

Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) and endogenous antioxidants, plays a central role in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). The brain's high oxygen demand and abundance of polyunsaturated fatty acids make it particularly vulnerable to ROS-induced damage. Despite major advances in research, no disease-modifying treatments for PD are currently available. Consequently, increasing attention has been directed toward natural bioactive compounds with antioxidant and neuroprotective properties. Among these, essential oils (EOs), volatile plant-derived mixtures with documented antioxidant, anti-inflammatory, and neuroactive effects, are emerging as promising adjuvants for PD management. This review critically examines the antioxidant and neuroprotective effects of well-characterized EOs evaluated in both in vitro and in vivo models of neurodegeneration. Literature searches were conducted in PubMed and Scopus up to March 2025, identifying studies investigating EOs or their major components in PD-related experimental settings. Evidence indicates that essential oils derived from the Citrus and Rosa genus, and the Lamiaceae family, can reduce intracellular ROS accumulation, inhibit lipid peroxidation, enhance endogenous antioxidant enzyme activity, and modulate both apoptotic and inflammatory pathways. These multitarget actions are often attributed to synergistic interactions among EO constituents, such as limonene, linalool, thymol, and carvacrol. Owing to their low toxicity and ability to cross the blood-brain barrier, EOs represent promising natural candidates for the development of complementary therapeutic strategies in PD. Further mechanistic and translational studies are warranted to substantiate their clinical potential.

Parkinson's disease (PD) is one of the most prevalent progressive neurodegenerative diseases today. However, existing treatments primarily focus on symptom management rather than attenuating disease progression and pathogenesis. ATP-sensitive potassium (K) ion channels play a significant role in motor control and coordination within the basal ganglia and have been implicated in the dopaminergic depletion mechanisms underlying PD. Recent studies have explored the potential of K channel inhibitors to slow PD pathogenesis and progression. Both pharmacological inhibition and genetic inactivation of these channels have been shown to reduce oxidative stress, dopamine (DA) depletion, and subsequent motor deficits. Contrastingly, alternative evidence suggests that K channel openers (KCOs) may elicit similar effects, highlighting the need for further exploration of K-mediated DA depletion mechanisms in PD. Future studies expanding our understanding of the mechanistic action of K in PD are essential to effectively leverage the channel's potential as a therapeutic target for combating PD pathology.

Glioma, particularly glioblastoma (GBM), represents the most aggressive primary brain tumor with limited treatment options and poor prognosis. Emerging evidence highlights ferroptosis induction as a promising therapeutic strategy, while long non-coding RNAs (lncRNAs) have gained attention as potential biomarkers and regulators in glioma pathogenesis. This study aimed to investigate the molecular mechanism of lncRNA Glial Cell Line-Derived Neurotrophic Factor Antisense RNA 1 (GDNF-AS1) in glioma cell ferroptosis through the LIM Homeobox 2 (LHX2)/Methyltransferase-Like 3 (METTL3)/Nuclear Receptor Coactivator 4 (NCOA4) pathway using Normal Human Astrocytes (NHA) and glioma cell lines (U87MG, T98G, U251, and A172), along with intracranial and subcutaneous xenotransplantation models established in BALB/c nude mice. Functional experiments demonstrated that GDNF-AS1, LHX2, and NCOA4 were downregulated while METTL3 was upregulated in glioma cells. GDNF-AS1 overexpression promoted mitochondrial damage and oxidative stress by enhancing ferroptosis, ultimately impairing glioma cell biological functions. METTL3 silencing augmented GDNF-AS1's effects, further exacerbating ferroptosis and oxidative stress while inhibiting glioma progression. Mechanistically, GDNF-AS1 recruited transcription factor LHX2 to upregulate its enrichment at the METTL3 promoter, thereby suppressing METTL3 transcription, reducing N6-Methyladenosine (m6A) levels, promoting NCOA4 expression, and inducing ferroautophagy and ferroptosis in glioma cells. These findings demonstrate that GDNF-AS1 inhibits glioma development by activating ferroptosis through the LHX2/METTL3/NCOA4 axis.

Traumatic brain injury (TBI) occurs when an external mechanical force damages brain tissue, leading to temporary or lasting disturbances in brain structure and function. The heterogeneous molecular and phenotypic nature of TBI poses a major challenge to translating basic research discoveries into clinically effective interventions. Emerging evidence indicates that epigenetic and epitranscriptomic mechanisms, including histone modifications, DNA methylation, and RNA modifications, play pivotal roles in the molecular response to TBI. In this review, we discuss post-TBI epigenomic alterations with a focus on histone modifications, DNA methylation, and RNA modifications, and we highlight preclinical interventions that modulate these alterations and improve related post-TBI behavioral outcomes.

The neuregulin-ERBB4 pathway is essential for maintaining cellular function. Upon stimulation by its ligand, neuregulin, ERBB4-a receptor tyrosine kinase-triggers multiple cellular responses, including proliferation, apoptosis, differentiation, and neuromuscular junction formation. Previous research has implicated dysregulated ERBB4 signaling in the pathophysiology of several neurodegenerative disorders, such as Alzheimer's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and Parkinson's disease. In this study, we examined ERBB4 expression in diseases characterized by phosphorylated tau (MAPT) pathology. We found that ERBB4 colocalized with neuronal and glial phosphorylated tau-positive inclusions in multiple tauopathies, including Pick's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutation. Conversely, ERBB4 did not colocalize with α-synuclein aggregates in α-synucleinopathies (Parkinson's disease and multiple system atrophy) or with neuronal intranuclear inclusions in triplet repeat disorders (Huntington's disease and dentatorubral-pallidoluysian atrophy). A co-immunoprecipitation assay indicated that ERBB4 can interact with tau intracellularly. Notably, in corticobasal degeneration, we observed ectopic ERBB4 expression in astrocytes lacking apparent phosphorylated tau aggregates. These findings suggest a potential role for ERBB4 in the pathophysiology of tau-related neurodegenerative diseases.