This review provides an in-depth exploration of the intricate energy metabolism pathways within the brain, with a particular focus on the dynamic interplay between neurons, astrocytes, and microglia. Neurons, with their high energy demands, primarily rely on oxidative phosphorylation and the tricarboxylic acid (TCA) cycle to sustain synaptic activity and neurotransmitter synthesis. In contrast, astrocytes predominantly engage in glycolysis, producing lactate and glutathione, which are essential for supporting neuronal function and protecting against oxidative stress. Additionally, microglia, the brain’s resident immune cells, exhibit a metabolic flexibility that allows them to shift between oxidative phosphorylation and glycolysis, depending on their activation state, which significantly influences neuroinflammation and synaptic plasticity. The review highlights the critical role of astrocyte-neuron metabolic coupling, particularly through the lactate shuttle and glutathione metabolism, in maintaining neuronal homeostasis and facilitating synaptic function. It also delves into the metabolic underpinnings of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis, illustrating how disruptions in brain energy metabolism contribute to disease progression. By synthesizing recent findings, this review not only underscores the centrality of brain energy metabolism in both normal and pathological conditions but also identifies potential therapeutic targets aimed at modulating these metabolic pathways to mitigate the effects of neurodegenerative disorders. This comprehensive analysis offers valuable insights that could propel further research and innovation in the field of neurology, making it essential reading for experts interested in the molecular mechanisms underlying brain function and disease.

Dravet Syndrome (DS), a rare genetic encephalopathy characterized by severe drug-resistant epilepsy and progressive neurodevelopmental regression in infancy, is caused by de novo mutations in the SCN1A gene on chromosome 2q24 in over 80% of cases. This review synthesizes current insights into its molecular pathogenesis, precision diagnostics, and therapeutic innovations: SCN1A mutations disrupt Nav1.1 sodium channel expression and membrane trafficking in GABAergic interneurons through transcriptional dysregulation, pre-mRNA splicing defects, and gating dysfunction, thereby impairing inhibitory synaptic transmission and disrupting brainwide excitatory-inhibitory balance. Notably, polygenic interactions (e.g., DEPDC5, CHD2 variants), astrocytic calcium signaling aberrations, and mitochondrial metabolic deficits synergistically exacerbate network hyperexcitability. Diagnostic advancements include a stratified framework integrating early febrile seizure phenotypes, comprehensive SCN1A sequencing (including deep intronic variants), and multimodal assessments (e.g., γ-band EEG power analysis and hippocampal volumetry), which significantly accelerate clinical diagnosis and reduce misdiagnosis. Therapeutic strategies are evolving from empirical seizure control to mechanism-targeted interventions: antisense oligonucleotides (ASOs) restore SCN1A transcript integrity by blocking pathogenic exon inclusion; adeno-associated virus (AAV9)-mediated activation of GABAergic neuron-specific SCN1A promoters and CRISPR/dCas9-driven endogenous Nav1.1 upregulation have both been shown to improve inhibitory synaptic function and elevate seizure thresholds in preclinical models. Additionally, novel molecules such as the Nav1.1-selective agonist Hm1a and 5HT₂BR receptor modulators offer new avenues by remodeling neuronal electrophysiology and neurotransmitter homeostasis. By dissecting the multi-dimensional molecular networks underlying DS and highlighting interdisciplinary integration of diagnostic-therapeutic technologies, this review provides a theoretical foundation for developing SCN1A-centric precision medicine, advocating a shift from symptomatic management to mechanism-driven interventions in clinical practice.

Epilepsy (EP) is a neurological disorder characterized by abnormal, sudden neuronal discharges. Seizures increase extracellular glutamate levels, causing excitotoxic damage. Glutamate transporter type 1 (GLT-1) and its human homologue excitatory amino acid transporter-2 (EAAT2) clear 95% of extracellular glutamate. Studies on neurodegenerative diseases suggest that trichostatin A (TSA), a broad-spectrum histone deacetylase (HDAC) inhibitor, can increase GLT-1/EAAT2 transcription. However, the precise mechanism by which TSA modulates GLT-1/EAAT2 levels remains unclear. This research demonstrated that TSA increases GLT-1/EAAT2 expression through histone acetylation, exerting substantial antiepileptic effects. Our results identify a promising therapeutic strategy for EP involving the modulation of glutamate transporters to mitigate seizures. Future research should explore the specific mechanisms underlying the effects of TSA and its potential clinical applications. Acute and chronic EP models were induced using kainic acid (KA) to assess the effects of TSA on the seizure threshold and frequency. Electrophysiological recordings of the hippocampus were used to evaluate the impact of TSA on neuronal excitability. RNA-Seq was used to analyse changes in glutamate transporter-related gene expression. Western blot analysis and qRT‒PCR were used to assess the influence of TSA on HDAC expression. To validate the role of GLT-1/EAAT2 in the antiepileptic effects of TSA, the impact of the GLT-1/EAAT2 inhibitor dihydrokainic acid (DHK) on the effects of TSA was assessed. Glutamate release was measured, and microdialysis was used to determine the glutamate content in the cerebrospinal fluid. Finally, metabolomics analysis was used to explore changes in amino acid levels in the hippocampus following TSA treatment to further confirm the antiepileptic potential of TSA. TSA effectively inhibited seizures in both acute and chronic models. It reduced the amplitude of excitatory postsynaptic currents (PSCs) and the frequency of spontaneous excitatory PSCs in the hippocampus without affecting inhibitory PSCs. Transcriptome analysis was used to identify glutamate transmission-related targets and revealed significant upregulation of the GLT-1 and EAAT2 genes in the hippocampus, which was confirmed by qRT‒PCR and Western blotting. Acetylation-induced upregulation of GLT-1/EAAT2 was observed, and inhibition of these transporters by DHK reduced the seizure-mitigating effects of TSA, underscoring the role of GLT-1/EAAT2 in clearing glutamate and its contribution to the observed antiepileptic effects of TSA. Our findings highlight the crucial role of GLT-1/EAAT2 in mediating the impact of TSA on glutamatergic transmission and seizure activity. These insights pave the way for the development of novel therapeutic approaches for EP involving the modulation of glutamate transporters.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a dismal 5‑year survival rate of ~9%, primarily due to late diagnosis, aggressive metastasis and profound resistance to conventional therapies. Epithelial‑mesenchymal transition (EMT) has been identified as a pivotal driver of these malignant phenotypes, facilitating early invasion, dissemination and treatment failure. The present review systematically elaborated on the multidimensional mechanisms underlying EMT in PDAC, emphasizing its operation as a spectrum of hybrid epithelial/mesenchymal states rather than a binary switch. Key molecular mechanisms include the activation of core transcription factors (such as Snail, ZEB, Twist), intricate crosstalk within the tumor microenvironment (such as transforming growth factor-β and hepatocyte growth factor signaling from stromal cells) and dynamic epigenetic reprogramming. Furthermore, EMT critically contributes to the acquisition of cancer stem cell properties and enhances the survival and colonization of circulating tumor cells. The present review also outlined emerging translational strategies targeting EMT‑related pathways, highlighting agents such as STNM01 that have entered early-phase clinical trials. By synthesizing unprecedented insights into EMT's plastic spectrum states and subtype‑specific regulatory networks, this work establishes a paradigm‑shifting framework for advancing EMT‑targeted therapies; offering transformative potential to overcome PDAC's historical therapeutic barriers and substantially improve patient survival outcomes. By synthesizing current insights from molecular pathways to therapeutic applications, the present review confirmed EMT as a promising therapeutic target and provides a strategic framework for advancing PDAC treatment, with the ultimate goal of improving clinical outcomes.