Glioblastoma remains a highly aggressive brain tumour with poor prognosis despite advances in standard therapies. The tumour microenvironment, comprising tumour cells, immune cells - predominantly tumour-associated micro...Glioblastoma remains a highly aggressive brain tumour with poor prognosis despite advances in standard therapies. The tumour microenvironment, comprising tumour cells, immune cells - predominantly tumour-associated microglia and macrophages (TAMMs) and extracellular matrix components, critically influences tumour progression and therapy resistance. TAMMs promote immunosuppression, tumour invasion, and angiogenesis, while T cells, although fewer, are suppressed by glioblastoma-mediated mechanisms, limiting anti-tumour immunity. Advances in non-invasive imaging technologies, including magnetic resonance imaging, positron emission transmission (PET), and optical methods, enable visualisation and characterisation of the immune microenvironment in vivo. Imaging agents targeting TAMM markers such as TSPO, CD163, CD68, CD206, and CX3CR1 have facilitated the mapping of immune cell distribution and functional states within gliomas. Additionally, emerging PET tracers allow monitoring of T-cell infiltration, activation, and exhaustion, providing insights into immunotherapy responses. Despite challenges such as blood brain barrier permeability, tracer specificity, and regulatory hurdles, multimodal imaging combined with radiomics and spatial transcriptomics offers promising avenues for personalised therapeutic strategies. Future directions focus on integrating immune cell imaging with theranostic approaches, nanoparticle delivery systems, and longitudinal monitoring to overcome tumour heterogeneity and improve treatment efficacy. This review highlights the evolving landscape of immune cell imaging in gliomas, emphasising its potential to enhance diagnosis, guide immunotherapy, and ultimately improve patient outcomes.
Wandering behavior or becoming lost in familiar environments is frequently observed during progression of Alzheimer's Disease (AD) and may be a possible prodromal symptom of the disease but also is extremely dangerous fo...Wandering behavior or becoming lost in familiar environments is frequently observed during progression of Alzheimer's Disease (AD) and may be a possible prodromal symptom of the disease but also is extremely dangerous for those suffering from this neurodegenerative disease. The accumulation of amyloid-beta peptide (Aβ) has been implicated in the neuropathology and cognitive deficits associated with AD. This study investigated changes in open field movement organization in a 5xFAD mouse model of AD that and the deposition of amyloid pathology. Mouse open field behavior was collected under dark and light conditions at three, six, nine, and twelve months of age. The resulting pattern of genotype differences consisted of a motor deficit rather than impaired use of self-movement or environmental cues. This work establishes a foundation for future studies to investigate the efficacy of therapeutic interventions.
The aim of the study is to investigate age-related changes in hippocampal subfield volumes and their associations with cognitive performance in a healthy Indian population. This study included 108 healthy participants di...The aim of the study is to investigate age-related changes in hippocampal subfield volumes and their associations with cognitive performance in a healthy Indian population. This study included 108 healthy participants divided into three age groups: younger (G1, 25-40 years, n = 38), middle (G2, 41-55 years, n = 30), and older (G3, 56-85 years, n = 40). Our results showed that auditory verbal learning (AVL), AVL immediate and delayed recall, and DSST scores were significantly lower in older adults. In contrast, trait anxiety was significantly higher in younger adults compared to G2 and G3, while perceived stress was higher in G1 and G2 compared to G3. Logical memory and sleep did not differ among the groups. Hippocampal subfield volumes were significantly reduced in G3, including bilateral subiculum and pre-subiculum, right para-subiculum, bilateral CA1, CA4, left CA3, bilateral GC-ML-DG, molecular layer, fimbria, and total hippocampal volume, whereas volumes remained stable in younger and middle-aged groups. Partial correlation analysis showed bilateral CA1, CA3, and Granule Cell -Molecular Layer of Dentate Gyrus (GC-ML-DG) volumes were significantly associated with auditory verbal learning and memory, bilateral GC-ML-DG with visuo-spatial coordination and psychomotor speed, and bilateral whole hippocampus with auditory verbal learning. Our findings demonstrate the decreased hippocampal subfield volume in elderly may be a common age-related neuropathological process, suggesting diminished neurogenesis and demyelination. These volumetric changes occur primarily in the elderly group and are relatively stable in other two groups indicating that decline in hippocampal subfield volumes begin only after midlife, leading to poor learning and memory performance. This study may be helpful for better understanding of the role of hippocampal subfields in learning and memory and suitable interventions thereof.
Former ERP studies have shown that linear distance (number of intervening words between two agreeing elements in a sentence) modulates P600 amplitude for gender agreement violations. However, these studies have primarily...Former ERP studies have shown that linear distance (number of intervening words between two agreeing elements in a sentence) modulates P600 amplitude for gender agreement violations. However, these studies have primarily focused on across-phrase dependencies, making it difficult to tease apart the effects of linear distance from those of structural distance (number of intervening phrases between two agreeing elements in a sentence). Norwegian, an understudied language in gender processing literature, permits manipulation of linear distance while holding structural distance constant. We tested 36 native Norwegian speakers with EEG, comparing three violation types: noun-suffix (within-word), determiner-noun (within-phrase), and noun-predicative adjective (across-phrase). Our aims were to: 1) assess processing of within-word gender violations, which, to our knowledge has not previously been done; 2) examine the effect of linear distance on within-phrase gender agreement by comparing processing of noun-suffix and determiner-noun dependencies; and 3) establish an ERP baseline for Norwegian gender processing. All three violation types elicited P600 responses, indicating repair/reanalysis processes. Noun-predicative adjective violations additionally produced a left anterior negativity, and determiner-noun violations showed a late frontal negativity. The noun-suffix P600 demonstrates that within-word gender violations recruit similar repair mechanisms as between-word violations. Moreover, the noun-suffix P600 was larger than the determiner-noun P600, likely due to either weaker constituent links resulting from longer distance, or longer distances reducing repairs due to a cost-benefit tradeoff. The findings from this study show that 1) within-word violations engage the same reanalysis processes as between-word violations, 2) within-phrase gender agreement processing is sensitive to linear distance, and 3) Norwegian exhibits similar ERP correlates of gender processing as those found for other languages.
To investigate structural and functional alterations in the prefrontal cortex-hippocampus (PFC-HPC) circuit in temporal lobe epilepsy (TLE) and the regulatory effects of cortical electrical stimulation on hippocampal act...To investigate structural and functional alterations in the prefrontal cortex-hippocampus (PFC-HPC) circuit in temporal lobe epilepsy (TLE) and the regulatory effects of cortical electrical stimulation on hippocampal activity. A kainic acid (KA)-induced TLE mouse model was used. Diffusion tensor imaging (DTI) analyzed PFC-HPC structural connectivity. Optimized PFC-HPC brain slices were prepared for electrophysiological recording via high-density microelectrode arrays (HD-MEAs), and cortical electrical stimulation at different intensities was applied. DTI revealed abnormal diffusion metrics fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and the number of whole-brain fiber tracts in epileptic mice. Electrophysiologically, epileptic slices showed enhanced low-frequency oscillations, reduced high-frequency oscillations, impaired cross-frequency coupling (CFC), and disrupted neuronal firing in the HPC. Notably, cortical electrical stimulation at 20μA and 100μA primarily improved pathological neural oscillations and theta-gamma CFC in the hippocampus, while stimulation at 60μA specifically normalized the abnormal action potential dynamics of hippocampal neurons. This study demonstrates structural and functional remodeling of the PFC-HPC circuit in TLE, and cortical electrical stimulation modulates pathological hippocampal activity, providing insights into non-invasive deep neuromodulation strategies in TLE. NEW & NOTEWORTHY This study explores the structural changes in PFC-HPC connectivity and the regulatory effect of cortical electrical stimulation on hippocampal neural activity in brain slices of mice with TLE, with key findings showing that TLE mice exhibit structural alterations in PFC-HPC connectivity, and epileptic PFC and HPC present dysregulated neural oscillations, cross-frequency coupling, and neuronal firing. Additionally, cortical stimulation exerts an intensity-specific modulation effect: stimulation with 20μA or 100μA normalizes oscillations, while stimulation with 60μA regulates action potential. These results provide valuable insights into the development of non-invasive deep neuromodulation strategies for TLE.
Cortical spreading depolarization (CSD) has been implicated in neurological disorders, such as migraine, traumatic brain injury, and stroke. Since neurovascular and inflammatory responses of the cerebral cortex associate...Cortical spreading depolarization (CSD) has been implicated in neurological disorders, such as migraine, traumatic brain injury, and stroke. Since neurovascular and inflammatory responses of the cerebral cortex associated with CSD play a critical role in the exaggeration and expansion of the lesions, understanding the molecular mechanisms underlying these phenomena would be indispensable for the development of therapeutic interventions for disorders with CSD. Given that the mitochondrial protein, translocator protein 18 kDa (TSPO), plays a role in cellular metabolism and inflammation, we hypothesized that TSPO can modulate the susceptibility of the brain to CSD. To address this issue, we examined the physiological and molecular changes in cortical tissue under the influence of evoked CSD in TSPO-knockout mice. Histological analysis corroborated that TSPO-knockout mice developed six-layered structures with neuronal and glial cells comparable with those in wild-type mice. In vivo electrophysiology under anesthesia showed that mice with TSPO deletion reduced the number of CSD generation compared with the control group. This change in the CSD was associated with impaired induction of inflammatory genes such as IL-1β, Cox2, and Ccl2. Interestingly, TSPO gene deletion had a protective effect on CSD-induced disruption of the blood-brain barrier function with less extravasation of the Evans blue administered systemically. Collectively, these results highlighted a novel role of TSPO in neurovascular and inflammatory responses as sequelae of CSD.
Doxorubicin (DOX) is a widely used chemotherapeutic agent whose clinical application is limited by severe neurotoxic side effects, manifesting as cognitive dysfunction and neuronal injury following both acute and chronic...Doxorubicin (DOX) is a widely used chemotherapeutic agent whose clinical application is limited by severe neurotoxic side effects, manifesting as cognitive dysfunction and neuronal injury following both acute and chronic exposure. Neuroinflammation, oxidative stress, and apoptosis are central mechanisms underlying DOX-induced neurotoxicity. Melittin, a bioactive neuropeptide derived from bee venom, has demonstrated potent anti-inflammatory and cytoprotective properties; however, its effects on DOX-induced neurotoxicity remain insufficiently characterized. Mice were assigned to acute (DOX-4) and chronic (DOX-3) exposure protocols. Melittin was administered at doses of 0.1, 0.2, and 0.4 mg/kg. Neuroprotective efficacy was evaluated through biochemical markers of oxidative stress, including malondialdehyde (MDA) and reduced glutathione (GSH). Additionally, neuroinflammation (NF-κB, iNOS, nNOS, TNF-α, IL-6) and apoptosis (Caspase-3) were assessed via immunohistochemical and molecular analyses in brain tissue. In the present study, we investigated the neuroprotective effects of melittin in murine models of acute and chronic DOX-induced neurotoxicity. Male Balb/c mice were exposed to acute (4 mg/kg, 2 weeks) or chronic (3 mg/kg, 6 weeks) DOX administration, with melittin (0.1, 0.2, or 0.4 mg/kg) administered intraperitoneally prior to DOX administration. Molecular alterations were evaluated in brain tissue by quantitative real-time PCR analysis of NF-κB, TNF-α, IL-6, inducible and neuronal nitric oxide synthases (iNOS, nNOS), and caspase-3. Neuroprotective efficacy was evaluated through biochemical markers of oxidative stress, including malondialdehyde (MDA) and reduced glutathione (GSH). Finally, NF-κB protein expression was further assessed by immunohistochemistry. DOX administration significantly upregulated pro-inflammatory cytokines, NF-κB signaling, MDA level, iNOS and caspase-3 expression, while suppressing nNOS expression and GSH level in both acute and chronic neurotoxicity models. Melittin treatment markedly attenuated DOX-induced neuroinflammatory and apoptotic responses in a dose-dependent manner, with the highest dose restoring molecular parameters toward control levels. These protective effects were more pronounced in the chronic neurotoxicity model. Our findings demonstrate that melittin exerts a robust neuroprotective effect by modulating the oxidative-inflammatory-apoptotic axis and restoring redox homeostasis in the brain. Melittin may represent a promising neuropeptide-based therapeutic strategy for mitigating chemotherapy-associated neurotoxicity.
Perceptual decisions are systematically biased by recent history, producing both attractive and repulsive forms of serial dependence. Previous work suggests that interrupting the perception-action cycle by omitting a res...Perceptual decisions are systematically biased by recent history, producing both attractive and repulsive forms of serial dependence. Previous work suggests that interrupting the perception-action cycle by omitting a response may reduce attractive biases and enhance repulsive ones, but the neural mechanisms underlying this effect remain unclear. Here, we investigated the EEG correlates of response-requirement effects in serial dependence during visual orientation judgments. Following noresponse trials, we confirmed reduced attractive and increased repulsive biases. In parallel, these trials elicited stronger evoked responses on subsequent trials and enhanced neural representations compared with response trials. These findings indicate that interrupting the perception-action cycle promotes a state of reengagement with current sensory input, reshaping the balance between attractive and repulsive serial dependence, and giving rise to distinct electrophysiological signatures.
Glioblastoma (GBM) remains a therapeutic challenge due to its resistance to standard chemotherapy and high recurrence rate. This study investigates the combined effects of alantolactone (ALT) and temozolomide (TMZ) on GB...Glioblastoma (GBM) remains a therapeutic challenge due to its resistance to standard chemotherapy and high recurrence rate. This study investigates the combined effects of alantolactone (ALT) and temozolomide (TMZ) on GBM cells, focusing on stemness, lipid metabolism, and the underlying Hippo signaling pathway. Human GBM cell lines U87 and U251 were treated with ALT and TMZ, either alone or in combination. Cell viability was assessed using the CCK-8 assay, stemness was evaluated by sphere formation assay, and gene and protein expression were analyzed by qPCR and Western blotting. A xenograft mouse model was established to evaluate in vivo efficacy. Phospho-kinase arrays and rescue experiments using the Hippo pathway inhibitor XMU-MP-1 were performed to explore the underlying mechanisms. The results showed that both ALT and TMZ inhibited cell proliferation in a dose-dependent manner. The combination treatment synergistically reduced cell viability, sphere formation, and the expression of stemness markers (CD133, NANOG, SOX2) and lipid metabolism regulators (PLIN2, FASN, SREBP1). In vivo, combined therapy significantly suppressed tumor growth and improved histopathological features. Mechanistically, ALT and TMZ promoted YAP1 phosphorylation and downregulated TEAD2, AXL, and c-MYC. Inhibition of Hippo signaling with XMU-MP-1 reversed the anti-tumor effects of the combination treatment. In conclusion, ALT and TMZ synergistically inhibit GBM growth and stemness by activating the Hippo pathway and suppressing lipid metabolism. These findings provide a rationale for the combined use of ALT and TMZ as a potential therapeutic strategy against GBM.
This study investigated frequency-specific cortical activity associated with different mirror feedback (MF) tasks during bilateral robot-assisted arm movement, using a virtual reality-based mirror system and electroencep...This study investigated frequency-specific cortical activity associated with different mirror feedback (MF) tasks during bilateral robot-assisted arm movement, using a virtual reality-based mirror system and electroencephalography. Eighteen healthy right-handed participants performed bimanual robot-assisted wrist-extension movements, with the passive hand driven by the active hand via a bimanual robot-assisted training device. Four experimental conditions were tested: congruent MF, incongruent MF, static virtual mirrored hand, and blank screen. Our results demonstrated that both congruent and incongruent MF elicited sustained activation of the mirror neuron system, as reflected by prolonged alpha event-related desynchronization (ERD). In the low-beta band, MF tasks enhanced proprioceptive processing, evidenced by stronger ERD in centroparietal and parietal regions relative to the blank screen and static hand conditions during the first 2000 ms after movement onset. Additionally, attenuation of beta rebound in frontocentral and parietal regions under MF conditions suggested continued motor cortical engagement beyond movement termination. Selective modulation in the high-beta band was observed in the congruent MF condition, with significantly greater ERD in bilateral posterior parietal cortices and the left posterior parietal cortex relative to static hand and blank screen conditions, indicating enhanced visuomotor integration when visual feedback was congruent with motor output. Overall, these findings reveal that VR-based MF not only sustains mirror neuron system activation and enhances proprioceptive feedback but also modulates post-movement beta dynamics and facilitates visuomotor integration. The observed frequency-specific oscillatory signatures provide neurophysiological evidence supporting the integration of VR-based MF into rehabilitation protocols aimed at improving motor and sensory function, particularly for patients with stroke.
OBJECTIVES: To evaluate the clinical efficacy of acupuncture combined with Jieyu Huoxue Formula in treating OA of the liver depression and qi stagnation type, and to assess associated changes in hemorheology and retrobul...OBJECTIVES: To evaluate the clinical efficacy of acupuncture combined with Jieyu Huoxue Formula in treating OA of the liver depression and qi stagnation type, and to assess associated changes in hemorheology and retrobulbar blood flow. METHODS: 80 patients diagnosed with liver depression and qi stagnation type OA were enrolled and randomly assigned to two groups (n = 40 per group). The control group received standardized treatment with oral mecobalamin tablets, while the combined treatment group received acupuncture in conjunction with the oral administration of Jieyu Huoxue Formula. Clinical efficacy, visual acuity, hemorheological parameters, and retrobulbar blood flow were compared between the two groups. RESULTS: Following treatment, 26 patients in the control group and 11 patients in the combined treatment group exhibited no significant therapeutic response. The overall efficacy rate in the combined treatment group was significantly higher than that observed in the control group (p < 0.05). Post-treatment, the combined treatment group demonstrated significantly greater improvement in visual acuity compared to the control group (p < 0.05). Additionally, significant reductions in whole blood viscosity and increases in peak systolic velocity of retrobulbar blood flow were observed in combined treatment group relative to controls (both p < 0.05). CONCLUSIONS: Acupuncture combined with Jieyu Huoxue Formula yielded superior therapeutic outcomes in patients with liver depression and qi stagnation type OA. The combined intervention improved visual acuity, reduced whole blood viscosity, and enhanced retrobulbar blood flow, indicating a protective effect on the optic nerve.
Microglia-mediated neuroinflammation is increasingly recognized as a contributor to neurodegenerative disease progression. However, how microglia contribute to neuroinflammation-induced cognitive dysfunction remains uncl...Microglia-mediated neuroinflammation is increasingly recognized as a contributor to neurodegenerative disease progression. However, how microglia contribute to neuroinflammation-induced cognitive dysfunction remains unclear. Galectin-3 (Gal-3) is a microglia-enriched lectin that regulates inflammatory signaling and phagocytosis, a plausible mediator linking neuroinflammation to cognitive dysfunction. In a lipopolysaccharide (LPS)-induced mouse model of neuroinflammation (0.5 mg/kg for 7 consecutive days), cognitive function was evaluated using the open field, Y-maze, and novel object recognition tests. In vivo CA1 extracellular electrophysiological recordings were used to analyze local field potentials (LFPs) and single-unit spiking activity. Dendritic morphology was evaluated by Golgi staining, and synaptic markers were quantified by immunofluorescence. In hippocampal CA1, microglia exhibited increased Gal-3 expression, enhanced phagocytic activity, and selectively increased engulfment of excitatory synapses. Systemic pharmacologic inhibition with TD139 and microglia-targeted Lgals3 knockdown (AAV-shLgals3 in Cx3cr1-CreERT2 mice) preserved excitatory synapses, restored CA1 gamma power, and improved cognitive performance in the neuroinflammation model. These results identify Gal-3-dependent microglial phagocytosis as a key mechanism linking neuroinflammation to cognitive dysfunction.
Thyrotropin-releasing hormone (TRH) is a hypothalamic neuropeptide that directs the thyroid axis function. Beyond this classical role, TRH is also synthesized in extrahypothalamic brain regions, where it is implicated wi...Thyrotropin-releasing hormone (TRH) is a hypothalamic neuropeptide that directs the thyroid axis function. Beyond this classical role, TRH is also synthesized in extrahypothalamic brain regions, where it is implicated with anorectic, anxiolytic and antiepileptic effects. Its anorectic role is supported by the reduced food intake of fasted rats when refed, after TRH is injected into their nucleus accumbens (NAc). The central nucleus of the amygdala (CeA) contains TRHergic cells, and its electrical stimulation (ES) induces a hypophagic effect on rats and transsynaptic changes in TRH content in the NAc and other brain regions. Since the G-protein-coupled type-1-TRH receptor is expressed in the NAc, we evaluated its participation in ES-amygdala-induced feeding regulation by using the electrical amygdaloid kindling model and by injecting antisense oligonucleotides (ASO) against type-1 TRH receptor (TRH-R1) in the NAc of rats. Male Wistar rats with an implanted electrode in CeA received daily ES (1 s, 60 Hz, 1 ms pulses) for seven days; then, fasted 48-h and on day 10, receiving a last ES, and refed for 2 h. Amygdala TRH mRNA expression was analyzed by in situ hybridization, while accumbal pro-TRH content by Western blot and immunohistochemistry. Amygdalar stimulation increased TRH mRNA in CeA, cortical amygdala and medial amygdalar nucleus; pro-TRH content increased in shell of NAc. Importantly, intra-NAc shell administration of ASO targeting TRH-R1, reversed the reduced food intake induced by CeA stimulation. These findings support the functional role of TRH-R1 in the NAc for the CeA electrical stimulation-induced hypophagia observed in re-fed fasted rats.
This study investigated the complex mechanisms underlying post-stroke depression (PSD) and the challenges associated with its clinical prevention and treatment. Specifically, it examined the effects of electroacupuncture...This study investigated the complex mechanisms underlying post-stroke depression (PSD) and the challenges associated with its clinical prevention and treatment. Specifically, it examined the effects of electroacupuncture at the "Siguan" acupoints on PSD and the relationship with the PERK-ATF4-CHOP endoplasmic reticulum stress (ERS) pathway. A rat model of PSD was established by combining middle cerebral artery occlusion (MCAO) with solitary rearing and chronic unpredictable mild stress (CUMS). Successfully modeled rats were randomly assigned to four groups: the model group, the electroacupuncture group, the drug group, and the sham operation group. The electroacupuncture group received 21 days of electroacupuncture at the "Siguan" acupoints (bilateral Hegu LI4 and Taichong LR3). Behavioral changes were assessed using a blinded method. Histopathological and molecular biological methods were then employed to comprehensively examine neuronal damage, apoptosis, and the expression of key proteins in the ERS pathway in the prefrontal cortex. The results showed that, compared with the model group, both electroacupuncture and medication significantly improved depressive‑like behavior, alleviated neuronal injury in the prefrontal cortex, and reduced apoptosis. At the molecular level, these effects were significantly associated with inhibition of the PERK-ATF4-CHOP ERS pathway, as evidenced by decreased levels of GRP78, p-PERK, CHOP, and downstream pro‑apoptotic proteins (Bax and cleaved caspase‑3). Notably, electroacupuncture demonstrated particular efficacy in promoting weight gain and modulating pathways such as p-PERK. These findings suggest that electroacupuncture at the "Siguan" acupoints may alleviate depressive‑like behavior in PSD rats by inhibiting the PERK-ATF4-CHOP pathway in the prefrontal cortex, thereby reducing endoplasmic reticulum stress‑induced neuronal apoptosis. This provides a novel potential molecular mechanism for electroacupuncture treatment of PSD.
Eukaryotic elongation factor 2 kinase (eEF2K) phosphorylates eukaryotic elongation factor 2 (eEF2) and slows translation elongation. In the nervous system, this pathway links neuronal activity, calcium signaling, energy...Eukaryotic elongation factor 2 kinase (eEF2K) phosphorylates eukaryotic elongation factor 2 (eEF2) and slows translation elongation. In the nervous system, this pathway links neuronal activity, calcium signaling, energy status, and stress responses to selective protein synthesis programs that shape synaptic plasticity, circuit excitability, and cell survival. Dysregulated eEF2K/eEF2 signaling has been implicated in epilepsy, Alzheimer's disease, Parkinson's disease, major depressive disorder, Down syndrome, and other brain conditions. However, the literature remains fragmented, largely preclinical, and often interpreted in an overly therapeutic manner. This review synthesizes the field using a mechanistic framework. Across disorders, altered eEF2 phosphorylation converges on five major axes: synaptic plasticity and excitatory/inhibitory balance, oxidative and mitochondrial stress responses, neuroinflammation/neuroimmune regulation, and aging-related neurogenesis and cognitive resilience. In chronic neurodegenerative and neurodevelopmental settings, excessive eEF2K activity is frequently associated with impaired de novo protein synthesis, synaptic dysfunction, and cognitive decline, whereas genetic or pharmacological suppression can improve selected behavioral and electrophysiological outcomes. By contrast, in acute metabolic stress or certain immune-cell contexts, eEF2K activity may serve adaptive and anti-inflammatory functions. These findings indicate that eEF2K has context-dependent, rather than uniformly pathogenic, roles. We also highlight major translational barriers, including dependence on rodent models, limited causal human data, incomplete cell-type resolution, and the off-target liabilities of commonly used inhibitors such as NH125 and A-484954. Overall, the eEF2K/eEF2 axis represents a biologically important but therapeutically complex target that will require selective, cell-aware, and stage-specific modulation. Future progress depends on better biomarkers, human models, and more selective brain-penetrant inhibitors.