Journal of Molecular Pathology

Background: Cholangiocarcinoma (CCA) has the highest incidence in Northeastern Thailand, where patients generally present with late diagnosis and poor prognosis. Opisthorchis viverrini (OV) infection is the major cause of CCA, with oxidative stress driving DNA mutations and genetic instability. Microsatellite instability (MSI) is a predictive biomarker in several cancers. This study aimed to investigate MSI status and its association with clinicopathological features and survival of CCA patients. Methods: Tissue and serum samples were collected from 25 surgical CCA patients. MSI status and mismatch repair (MMR) proteins were evaluated using an MSI scanner and immunohistochemistry (IHC). Serum OV IgG was assessed by ELISA, while tumor-infiltrating lymphocytes (TILs) were evaluated by two pathologists. Associations of MSI with clinicopathological features, OV status, MMR, and survival were analyzed. Results: Among CCA patients, 66.7% were MSI-high and 33.3% were MSI-low. MSI-high significantly correlated with age < 57 years, intraductal growth pattern, OV positivity, and early-stage disease. Patients with MSI-high and high TILs showed markedly improved median survival compared to MSI-low with low TILs (94.0 vs. 16.8 and 3.0 months; HR = 6.82 and 14.10; p = 0.004 and 0.001). Incorporation of MSI and TILs remained an independent prognostic factor in multivariate analysis (p < 0.05). Conclusions: MSI-high is highly prevalent in OV-associated CCA and is associated with intraductal growth, OV infection, and early-stage disease. Combined MSI and TIL status may serve as an independent prognostic factor, warranting validation in larger cohorts. Full article

Mpox, a zoonotic viral disease, has emerged as a global concern due to outbreaks in both endemic and non-endemic regions in 2022. Rodents, including African squirrels and Gambian pouched rats, are suspected key reservoirs, with human infections occurring through direct contact with infected animals or bushmeat consumption. Previously confined to rural Africa, mpox has spread via international travel and the exotic pet trade. Human-to-human transmission occurs mainly via respiratory droplets and direct contact with bodily fluids or lesions. The virus has a double-stranded DNA genome within a lipid envelope. Despite lower mutation rates in DNA viruses, mpox has developed mutations, particularly in genes like F8L, G9R, and F13L, facilitating viral replication and immune evasion. The virus targets immune cells such as monocytes and macrophages, weakening host defenses and prolonging infection. Immunocompromised individuals are at higher risk of severe complications. Although generally self-limiting, severe cases may require antiviral treatment. This article briefly summarizes the therapeutic and preventive strategies, and public health measures to combat zoonotic threats. Full article

Targetable gene alterations have become increasingly important in the treatment of cancers. Thirty STK11-mutated lung cancers from 199 cases with molecular profiling performed during 2016–2024 were studied for clinical, morphologic, immunohistochemical (IHC) and molecular features. Of the 30 STK11-mutated lung cancers, 29 were lung adenocarcinomas (LADCs) and 1 was large cell neuroendocrine carcinoma (LCNEC). STK11 mutation was not found in other subtypes of lung cancers. Of the 29 STK11-mutated LADCs, 6 (21%) were mucinous and 23 (79%) were non-mucinous. Of the 19 non-mucinous LADCs with sufficient material for IHC, 9 (47%) displayed acinar/papillary/lepidic patterns, 8 (42%) were poorly differentiated (solid/trabecular/basaloid/complex glandular), and 2 (11%) had mixed solid and acinar patterns. The most common concurrent altered genes were KRAS (52%), followed by TP53 (38%), KEAP1 (34%), and DNA repair genes (BRCA2/ATM) (21%). A total of 6/15 (40%) LADCs with a KRAS mutation presented with mucinous morphology. Concurrent EGFR, ROS, or ALK alterations with STK11 mutation were rare or non-existent. Of the 3 LADCs with SMARCA4 deficiency, 2 were mucinous and 1 had basaloid/adenoid cystic-like features. All the cases were microsatellite stable (MSS). The majority (55%) had low TMB (<10). Most (86%) had PD-L1 TPS 0 or <5%. Among the 14 non-mucinous LADCs with IHC performed, 5 (36%) were TTF-1-negative and all displayed poorly differentiated morphology. Overall, 8/10 (80%) of poorly differentiated components in non-mucinous LADCs were negative for TTF-1. In contrast, all LADCs with better differentiated patterns (acini/papillary/lepidic) were positive for TTF-1. The majority (14/21, 67%) of patients with available follow-up presented with metastasis. Full article

Introduction: Breast cancer is a heterogeneous malignancy influenced by diverse molecular profiles. The L-type amino acid transporter 1 (LAT1), encoded by the SLC7A5 gene, plays a key role in tumor metabolism, growth, and angiogenesis. Through its role in amino acid transport and activation of the mTORC1 signaling pathway, LAT1 has emerged as a potential therapeutic target. Objective: To evaluate SLC7A5/LAT1 expression and its association with clinicopathological parameters and molecular subtypes of invasive carcinoma of no special type (NST) in a Pakistani cohort. Methods: Eighty-three patients who underwent mastectomy or modified radical mastectomy for histologically confirmed primary invasive carcinoma of no special type were included. Immunohistochemistry was used to assess SLC7A5/LAT1 expression. Associations with clinicopathological features and molecular groups were analyzed using the Chi-square test. Results: The mean age of SLC7A5-positive patients were 48.4 ± 10.8 years. Overall, 24.1% of patients demonstrated SLC7A5 positivity. Although SLC7A5 expression was more frequent in cases categorized as having moderate or poor prognosis based on the Nottingham Prognostic Index (NPI), this trend was not statistically significant. Similarly, no significant associations were observed between SLC7A5 expression and other clinicopathological or molecular variables. Conclusions:SLC7A5/LAT1 expression was identified in approximately one-quarter of invasive breast carcinoma cases. Its expression appeared more common in tumors with poorer NPI categories, but without statistically verified associations. These findings suggest that SLC7A5 may act independently of conventional clinicopathological parameters. Larger, longitudinal studies with survival follow-up are required to clarify its prognostic and therapeutic significance. Full article

Background: The aim of this study was to determine Ezrin and MMP-2 immunohistochemical expressions in the gingival tissue of patients with or without diabetes and to determine the role of the molecular pattern involvement in the evolution of periodontal disease. Material and Methods: In this histological study, we investigated 53 subjects with periodontal disease (test group—27 patients with type 2 DM; control—26 patients without diabetes). Samples from both groups were subjected to the immunohistochemistry (IHC) technique to evaluate the immunoreactivity (IR) intensity of Ezrin and MMP-2. Results: Among diabetic patients with periodontitis, 55.4% of patients exhibited intensely positive expression (+++) of Ezrin, and 44.6% of patients showed moderate expression (++) of Ezrin. All patients with diabetes and periodontitis showed intensely positive expression for MMP-2. In contrast, the control group showed negative expressions of Ezrin and MMP-2 (-) in 100% of cases. Significant statistical differences were found between Ezrin and MMP-2 expression in gingival samples of diabetic patients and non-diabetic patients with periodontal disease (p < 0.05). Conclusions: Ezrin and MMP-2 are significantly overexpressed in patients with diabetes and stage 2–3 periodontitis compared with non-diabetic patients with periodontal disease. Ezrin showed an exclusive pattern of moderate to strong positive staining in the diabetes–periodontitis group and complete absence in controls. MMP-2 displayed a broader range of staining intensities, with a predominance of strong positivity in all locations. Ezrin may represent a more consistent discriminative marker, whereas MMP-2 reflects a wider spectrum of tissue activation related to inflammation and tissue remodeling. Full article

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors, clinically established for treating renal anemia, are emerging as potent immunomodulators with therapeutic potential far beyond erythropoiesis. This review dissects the mechanistic basis of their action, centered on the stabilization of hypoxia-inducible factor-alpha (HIF-α), a master transcription factor that orchestrates fundamental shifts in immune cell function. We synthesize evidence showing how HIF-α stabilization alters innate immunity, recalibrates T- and B-cell responses, and reshapes inflammatory signaling. This activity translates to significant efficacy in preclinical models of autoimmune disorders, organ fibrosis, and ischemia–reperfusion injury. However, their broader clinical translation is hindered by a critical paradox in oncology. While HIF-α can potentiate anti-tumor immunity, its sustained activation risks promoting malignancy by driving angiogenesis, metabolic reprogramming, and fostering an immunosuppressive tumor microenvironment. Addressing this duality, alongside the potential for long-term immune dysregulation, is paramount. Future development must therefore prioritize precision-targeting strategies to harness the therapeutic benefits of HIF-PHD inhibitors while mitigating their pro-tumorigenic liabilities. Full article

This research delves into the complex relationship between progenitor cells and the differentiated cell types that make up the stomach. It highlights the need for further investigation into the mechanisms governing stomach development and how these mechanisms relate to the maintenance of the stomach in a healthy state. The transition from normal gastric mucosa to metaplasia involves significant alterations in the phenotype and function of gastric epithelial cells, including stem cells, mucous neck cells, chief cells, and parietal cells. The presented literature review provides an in-depth analysis of pyloric and pseudopyloric metaplasia, along with spasmolytic polypeptide-expressing metaplasia, focusing on their biological significance, underlying pathogenesis, diagnostic features, and prognostic implications. It explores the role of various gastric epithelial cell types in the pathogenesis of metaplasia, highlighting recent advances in cellular plasticity, molecular pathways, and the implications for gastric carcinogenesis. Full article

Ependymomas are a heterogeneous group of central nervous system tumors originating from ependymal cells, exhibiting significant variability in clinical behavior, prognosis, and treatment response based on anatomical location and molecular profile. Historically, diagnosis and grading relied on histopathological features, often failing to predict outcomes accurately across tumor subtypes. With the integration of molecular and epigenetic profiling, the classification and management of ependymomas have undergone a significant transformation, culminating in the updated 2021 World Health Organization Classification of Tumors of the Central Nervous System. This molecularly driven system emphasizes the relevance of DNA methylation patterns and fusion oncogenes, offering a more biologically accurate stratification of disease. These insights enhanced diagnostic accuracy and informed prognostic assessments, paving the way for new targeted therapies. Although conventional treatment primarily consists of surgical resection and radiotherapy, emerging preclinical and early-phase clinical studies suggest a potential for molecularly guided interventions targeting specific oncogenic pathways. Despite these advances, effective targeted therapies remain limited, highlighting the need for further research and molecular stratification in clinical trial design. Additionally, the practical implementation of molecular diagnostics in standard-of-care settings is challenged by cost, accessibility, and institutional variability, which may impede equitable integration. This review summarizes the evolution of ependymoma classification, current molecular subtypes, gaps in clinical application and their implications for personalized therapy and future clinical research. Full article

Background: Since liquid-based cytology (LBC) has replaced the conventional Papanicolaou test in cervical cancer screening programs, pre-analytical procedures—particularly the choice of LBC collection media—have become crucial to ensure the accuracy of high-risk (HR) HPV DNA testing. This study aims to evaluate whether the newly developed CytoPath^® LBC medium can serve as a reliable alternative to standard solutions. Methods: This study exploited cell lines to evaluate the stability, integrity, and recovery rate of genomic DNA at different fixation time points (1, 7, 14 and 40 days) and serial dilutions (1:5, 1:10 and 1:20) extracted from cell lines. These samples have also undergone quantitative Real-Time PCR (qPCR) based HR-HPV test to assess the relative performance of the new preservative solution in detecting viral DNA with respect to the standard reference. Results: Cervical cell lines preserved in both media demonstrated consistent DNA stability over time. DNA yields were comparable between the two media. Notably, the DNA Integrity Number (DIN) was higher in samples fixed with the CytoPath^® solution. HR-HPV detection by qPCR showed equivalent performance, regardless of the fixative used. Conclusions: The CytoPath^® fixative solution represents a valid alternative to standard preservation media, offering improved DNA integrity while maintaining equivalent performance in HR-HPV qPCR testing. Full article

Background: Bone tissue decalcification is essential for histopathological evaluation, but conventional methods using inorganic acids degrade nucleic acids, limiting molecular testing. EDTA is known to better preserve DNA, but its suitability for next-generation sequencing (NGS) in clinical settings remains to be validated. Methods: This retrospective study evaluated 752 formalin-fixed paraffin-embedded (FFPE) tissue samples undergoing NGS between January 2022 and October 2024. Of these, 31 were decalcified using EDTA (Osteosoft, Merck, Germany). DNA was extracted using the Qiagen AllPrep^® kit and quantified using Qubit and NanoDrop. Libraries were prepared with a custom 30-gene Ampliseq panel and sequenced on the Ion Torrent platform. Sequencing was deemed suboptimal if <95% of target regions reached ≥250X depth. Results were compared to 721 non-decalcified FFPE samples. Results: Suboptimal sequencing occurred in 9.7% of EDTA-decalcified and 9.0% of non-decalcified cases (p = 0.9). DNA concentration (Qubit) and NanoDrop 260/280 ratios were not significantly different (p = 0.4 and p = 0.8, respectively), though EDTA cases had lower DNA concentrations (NanoDrop, p = 0.006) and 260/230 ratios (p = 0.002). Mutation detection in decalcified samples was consistent with known mutation profiles for respective tumor types. Conclusions: EDTA-decalcified FFPE bone tissues produce NGS results comparable to non-decalcified specimens, with similar sequencing success rates and acceptable DNA quality. These findings support the use of EDTA as a suitable decalcification method for molecular diagnostics, enabling broader inclusion of bone specimens in clinical testing. Full article

Cancer remains a leading global health challenge, with conventional diagnostic and treatment methods often lacking precision and adaptability. This review explores transformative advancements that are reshaping oncology by addressing these limitations. It begins with an overview of cancer’s complexity, emphasizing the shortcomings of conventional tools such as imaging and chemotherapy, which frequently fail to deliver targeted care. The discussion then shifts to biomarkers, which represent a groundbreaking frontier in early detection, enabling the identification of unique biological signatures that signal the presence of cancer with heightened sensitivity. Building on this foundation, the review examines personalized molecular therapies, which target the specific genetic and molecular vulnerabilities of tumors. These therapies not only enhance treatment efficacy but also minimize adverse effects, offering patients improved outcomes and quality of life. By integrating biomarker-driven diagnostics with tailored therapeutic strategies, a new paradigm of precision oncology emerges, bridging the gap between early detection and effective intervention. Real-world case studies highlight both successes, such as significantly improved survival rates, and persistent challenges, including accessibility and cost barriers. Looking ahead, the review outlines pathways by which to scale these innovations, emphasizing the critical need for robust infrastructure, sustained research investment, and equitable healthcare policies. It concludes by envisioning a future where biomarkers and personalized therapies converge to redefine cancer care, offering earlier detection, precise interventions, and better patient experiences. This work underscores the urgency of adopting cutting-edge approaches to overcome cancer’s persistent threats, paving the way for a more effective and humane era in oncology. Full article

Background/Objectives: The non-small-cell lung cancer (NSCLC) therapeutic landscape has undergone a profound transformation with the introduction of multiple personalized treatment options. Mutations in ERBB2 (HER2) have recently emerged as promising novel targets for the treatment of non-squamous NSCLC (nsNSCLC). Accurate, rapid, and efficient molecular profiling is crucial for identifying patients who may benefit from targeted therapies, including HER2-directed agents. Materials and Methods: Here, we aimed to retrospectively assess the performance of the Oncomine™ Precision Assay* (OPA) in combination with the Ion Torrent Genexus™ Integrated Sequencer* (Thermo Fisher Scientific. Waltham, MA, USA) for detecting ERBB2 mutations in nsNSCLC. A total of 108 archived nsNSCLC samples, consisting of biopsies, resections, and cytological specimens, were used to assess concordance with in-house-validated orthogonal tests. Results: The OPA showed high sensitivity and specificity with an overall accuracy of 100% for single-nucleotide variants (SNVs) and insertions and deletions (Indels). SNVs and Indels with allele frequencies as low as 5% were correctly identified across samples with a tumor cell content ranging from 5% to 95%. Additionally, the assay demonstrated high reproducibility across the six participating laboratories. The turnaround time of the OPA was notably shorter compared to traditional orthogonal methods, facilitating rapid molecular report generation. Conclusions: The OPA in combination with the Ion Torrent Genexus™ System allows for highly sensitive and specific detection of relevant ERBB2 mutations. The assay’s streamlined workflow, coupled with its automated data analysis pipeline, enables a fast turnaround time for testing across a range of sample types. This includes samples with reduced tumor cell content and limited available input. This study demonstrates the future potential of using this assay in a clinical setting. Full article

Sepsis is a complex and life-threatening syndrome arising from a dysregulated immune response to infection that can lead to severe organ dysfunction and increased mortality. This multifactorial condition is marked by intricate interactions between immune, inflammatory, and coagulation pathways, which together contribute to systemic effects and multiorgan damage. The aberrant immune activation seen in sepsis includes profound leukocyte activation, endothelial dysfunction, imbalanced coagulation leading to disseminated intravascular coagulation (DIC), and the production of both pro-inflammatory and anti-inflammatory mediators. These events culminate in pathological alterations that extend beyond the initial site of infection, adversely impacting distant tissues and organs. Early recognition and timely intervention are crucial to mitigate the progression of sepsis and its associated complications. This review aims to explore the underlying biological mechanisms, including host–pathogen interactions, immune dysregulation, and the cascade of systemic and organ-specific effects that define sepsis. By delving into the pathophysiological processes, we intend to provide insights into the determinants of multiorgan failure and inform strategies for therapeutic intervention. Understanding these mechanisms is pivotal for advancing clinical outcomes and reducing mortality rates associated with this critical condition. Full article

Pediatric high-grade glioma (pHGG) is a devastating group of childhood cancers associated with poor outcomes. Traditionally, diagnosis was based on histologic and immunohistochemical characteristics, including high mitotic activity, presence of necrosis, and presence of glial cell markers (e.g., GFAP). With advances in molecular tumor profiling, these tumors have been recategorized based on specific molecular findings that better lend themselves to prediction of treatment response and prognosis. pHGG is now categorized into four subtypes: H3K27-altered, H3G34-mutant, H3/IDH-WT, and infant-type high-grade glioma (iHGG). Molecular profiling has not only increased the specificity of diagnosis but also improved prognostication. Additionally, these molecular findings provide novel targets for individual tumor-directed therapy. While these therapies are largely still under investigation, continued investigation of distinct molecular markers in these tumors is imperative to extending event-free survival (EFS) and overall survival (OS) for patients with pHGG. Full article

Background: Methylene blue (MB), a versatile redox agent, is emerging as a promising therapeutic in diseases associated with mitochondrial dysfunction. Its ability to optimize the electron transport chain increases ATP synthesis (30–40%) and reduces oxidative stress, protecting cellular components such as mitochondrial DNA. The protective role of this compound has been described in several neurodegenerative disease such as Alzheimer’s and Parkinson’s diseases. However, its role in cardiovascular disease has been poorly explored. Methods: In this study, we explored the impact of MB on murine (HL1) and human (AC16) cardiomyocyte redox signaling and cellular survival using RT-Qpcr analysis and immunochemistry assays. Results: Our results revealed that MB increased functional mitochondria, reversed H₂O₂-induced oxidative damage, and modulated antioxidant gene expression. Furthermore, it regulated the microRNA16–UPR signaling axis, reducing CHOP expression and promoting cell survival. Conclusions: These findings underscore its potential in cardioprotective therapy; however, its putative use as a drug requires in vivo validation in preclinical animal models. Full article

Background: This study is the first to investigate the association between colorectal cancer (CRC) risk and the hMLH1 −93G>A and hMSH2 1032G>A polymorphisms of mismatch repair (MMR) genes in the Azerbaijani population. Methods: Peripheral blood samples containing EDTA were collected from the study subjects (134 patients and 137 controls), and genomic DNA was extracted using the non-enzymatic salting-out method. Genotypes were determined by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), and the results were visualized through agarose gel electrophoresis. Results: Overall, no statistically significant correlation was observed between CRC risk and the hMLH1 −93G>A polymorphism in the heterozygous GA (OR = 0.760; 95% CI = 0.374–1.542; p = 0.446), the mutant AA (OR = 1.474; 95% CI = 0.738–2.945; p = 0.270), or the A allele (OR = 1.400; 95% CI = 0.984–1.995; p = 0.062). However, in contrast to the dominant model, a statistically significant association was found between the recessive model and an increased CRC risk, with an odds ratio of 1.788 (95% CI = 1.102–2.900; p = 0.018). The hMLH1 −93G>A polymorphism was identified at a significantly higher frequency across the TNM stages, with the distribution showing statistical significance (p < 0.05). Additionally, no statistically significant association was observed between the hMSH2 1032G>A polymorphism and CRC risk. Conclusions: Although no overall association was observed for hMLH1 −93G>A, our findings suggest a potential link with increased colorectal cancer risk under the recessive model in the Azerbaijani population. Further studies are warranted to confirm this model-specific association and investigate the underlying biological mechanisms. Full article

Introduction: Thyroid cancer and obesity are prevalent conditions with significant global health implications. Differentiated thyroid cancer (DTC) is influenced by various molecular pathways, including those involving Transforming Growth Factor-Beta (TGF-β), a cytokine implicated in cell proliferation, differentiation, immune regulation, and fibrosis. Obesity (BMI > 30) has been associated with thyroid dysfunction and an increased incidence of nodular goiter. However, the relationship between TGF-β levels, thyroid malignancies, and metabolic disturbances remains unclear. This study aimed to analyze TGF-β1, -2, and -3 concentrations in blood serum before and after thyroidectomy in patients with DTC and obese individuals with nodular goiter to evaluate their potential role in thyroid pathology and obesity-related metabolic changes. Methods: A prospective study was conducted at a high-volume surgical center where over 700 thyroidectomy procedures are performed annually. Seventy-six consecutive patients (aged 26–79 years) were included: 21 with DTC and 55 with euthyroid nodular goiter. The latter group was subdivided based on BMI into obese (BMI > 30, n = 26) and non-obese (BMI < 30, n = 29) cohorts. Blood samples were collected preoperatively and on the first postoperative day for TGF-β quantification using the Bio-Plex Pro™ Human Cytokine Assay. Statistical analysis was performed using the Student’s t-test. Results: Postoperatively, patients with DTC exhibited significantly higher TGF-β1 (210,000 pg/mL), TGF-β2 (360 pg/mL), and TGF-β3 (170 pg/mL) levels compared to obese patients with nodular goiter (p < 0.05). In the nodular goiter group, BMI did not significantly influence preoperative TGF-β levels (p > 0.05). However, postoperatively, obese patients showed lower TGF-β1 (100,000 pg/mL) and TGF-β2 (30 pg/mL) levels compared to normal-weight individuals (p = 0.03), while no significant difference was observed for TGF-β3 (p > 0.05). Conclusions: The study highlights distinct alterations in TGF-β isoform levels in thyroid cancer and obesity. Elevated postoperative TGF-β levels in DTC patients suggest a role in tumor progression and response to surgical intervention. In contrast, the reduction of TGF-β1 and TGF-β2 levels in obese patients postoperatively may indicate a complex interplay between obesity, surgical stress, and cytokine regulation. These findings underscore the need for further research into the molecular mechanisms governing TGF-β dynamics in thyroid disorders and obesity, with potential implications for therapeutic interventions. Full article

Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric central nervous system (CNS) tumor that predominantly affects children under the age of 3. It is defined by the inactivation of the SMARCB1 gene, leading to the loss of INI1, a protein essential for cell lineage determination and cell differentiation. Current standard of care treatment requires aggressive multimodal therapy with maximal safe resection, high-dose chemotherapy with autologous stem cell rescue, and radiation, yet overall survival remains < 50%. These intensive regimens have improved overall survival but are associated with significant morbidity and long-term effects. Molecular profiling has significantly advanced the understanding of ATRTs, revealing four molecular subgroups, ATRT-TYR, ATRT-MYC, ATRT-SHH, and ATRT-SMARCA4, each with distinct clinical presentations, oncogenic pathways, and prognoses. Molecular characterization enables better prognostic stratification, guiding treatment decisions and allowing for more personalized therapeutic approaches. Targeted therapies based on these molecular insights remain experimental, and continued exploration of molecular mechanisms and how they differ amongst subgroups is pivotal for the development of less toxic, more effective targeted treatments. Full article

A balanced excitatory/inhibitory (E/I) tone is crucial for proper brain function, and disruptions can lead to neurological disorders. This review explores the role of astrocytes in maintaining a balanced E/I tone in the brain, which is crucial for proper functioning. It highlights the potential for dysfunctional astrocyte metabolism to disrupt E/I balance, leading to neuronal dysfunction and potentially causing neurological disease pathogenesis. The review focuses on glucose, lactate shuttling, and glutamate metabolism. This review synthesizes findings from in vitro, in vivo, and human studies examining the interplay between astrocyte metabolism, neuronal activity, and E/I balance. Literature searches were conducted using keywords including “astrocyte metabolism”, “excitatory/inhibitory balance”, “glutamate”, “lactate shuttle”, “neurometabolic coupling”, and “neurological disorders” in databases such as PubMed and Web of Science. Disruptions in astrocyte glucose uptake or glycolysis can impair lactate production, reducing neuronal energy supply and affecting neuronal excitability. Impaired glutamate uptake and conversion to glutamine within astrocytes leads to elevated extracellular glutamate, promoting excitotoxicity. Altered glycogen metabolism and other metabolic impairments within astrocytes can also affect neuronal health and contribute to imbalances between excitation and inhibition. Dysfunctional astrocyte metabolism represents a significant contributor to E/I imbalance in the brain. Understanding the specific metabolic vulnerabilities of astrocytes and their impact on neuronal function provides potential therapeutic targets for neurological disorders characterized by E/I dysregulation. Targeting astrocyte metabolism may offer a novel approach to restoring E/I balance and improving neurological outcomes. Full article