Metabolic brain disease最新文献

{"title":"Pentoxifylline targets TLR4/MyD88/NF-κB signaling to ameliorate neuroinflammation and metabolic dysfunction in a rat model of chronic hypoperfusion-induced vascular cognitive impairment.","authors":"Xiaohan Wang, Bingchuan Xie, Xiaoyang Yuan, Jiaying Rong, Xiaojing Lv, Qingying Ma, Li Shen, Bing Han","doi":"10.1007/s11011-026-01934-5","DOIUrl":"10.1007/s11011-026-01934-5","url":null,"abstract":"<p><p>Vascular cognitive impairment (VCI) driven by chronic cerebral hypoperfusion lacks disease-modifying therapy. We tested whether pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor with dual hemorheological and anti-inflammatory properties, attenuates VCI-like cognitive and inflammatory abnormalities in a rat model. Three-month-old male Sprague-Dawley rats underwent bilateral common carotid artery occlusion (BCCAO) or sham surgery. PTX (60 mg kg⁻1 day⁻1, gavage) or vehicle was administered for 28 days starting 24 h post-operation. Spatial cognition was assessed with the Morris water maze; neuronal injury, microglial activation, and glucose metabolism were evaluated by histology, immunofluorescence, 1⁸F-FDG PET/CT, and western blotting. Systemic and hippocampal cytokines were quantified by multiplex immunoassay; TLR4/MyD88/NF-κB signaling was profiled by RNA-seq and western blotting. BCCAO induced progressive cognitive deficits without sustained weight loss, paralleled by CA1 neuronal damage, microglial proliferation, and marked elevations of IL-1β, IL-2, IL-17, and TNF-α in plasma and hippocampus. PTX shortened escape latency, restored probe-trial platform crossings, preserved neuronal morphology, suppressed microglial Iba-1⁺/Ki67⁺ expansion, and reduced all four cytokines. Mechanistically, PTX down-regulated TLR4, MyD88, and NF-κB p65 mRNA and protein, reduced nuclear translocation of NF-κB p65, and partially reversed frontal and hippocampal glucose hypometabolism. Peripheral IL-1β and IL-17 levels correlated positively with cognitive impairment. Pentoxifylline concurrently mitigates hypoperfusion-associated neuroinflammation, neuronal injury, and glucose hypometabolism via inhibition of the TLR4/MyD88/NF-κB axis, supporting PTX as a readily translatable candidate for early VCI intervention.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148562468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.","authors":"Leanne Khoo, Khuen Yen Ng, Cien Leong Chye, Yi Ko, Jia Yee Lee, Yian Koh, Min Tze Tsen, Soi Moi Chye","doi":"10.1007/s11011-026-01911-y","DOIUrl":"10.1007/s11011-026-01911-y","url":null,"abstract":"<p><p>Aggregation of α-synuclein (α-Syn) is a defining pathological feature of Parkinson's disease (PD), contributing to progressive neuronal dysfunction and death. Unlike prior reviews focused predominantly on aggregation as an isolated endpoint, this review proposes a neurodevelopmental-neurodegenerative continuum as an interpretive framework, suggesting that α-Syn's physiological roles in synaptic development and circuit maturation may be linked to its later pathological behaviour. Within this context, we discuss recent advances in small-molecule strategies targeting key stages of α-Syn pathology, including synthesis, misfolding, aggregation, post-translational modification, and clearance. These include translation and misfolding inhibitors, aggregation modulators such as minzasolmin (UCB0599), epigallocatechin gallate and anle138b, as well as compounds that enhance α-Syn degradation through autophagy-lysosomal and ubiquitin-proteasome pathways. Additional strategies targeting proteostasis and mitochondrial dysfunction are also considered. Beyond its pathogenic role, α-Syn contributes to synaptic vesicle trafficking, neurotransmitter release, and neuronal maturation, and disruption of these functions may increase vulnerability to later neurodegeneration. In conclusion, small-molecule-based therapies represent a promising multi-targeted strategy for PD; however, key translational challenges and unresolved questions remain, including optimisation of pharmacokinetics, target specificity, and blood-brain barrier (BBB) penetration and validation in clinical settings.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148562437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic insights into migraine: mechanisms and biomarkers from in vivo and clinical studies.","authors":"Wattakorn Laohapiboolrattana, Nipon Chattipakorn, Siriporn C Chattipakorn","doi":"10.1007/s11011-026-01940-7","DOIUrl":"10.1007/s11011-026-01940-7","url":null,"abstract":"<p><p>Migraine is a complex neurological disorder characterized by recurrent attacks of moderate to severe headaches with nausea, photophobia, and phonophobia. Although advances in neuroimaging have improved diagnostic capabilities and options of treatment, the diagnosis and management of migraine still depend primarily on clinical symptoms. Many studies have reported that metabolomics, the comprehensive analysis of small-molecule metabolites, offers a promising approach for elucidating the neuro-pathophysiology and identifying novel biomarkers or therapeutic targets of migraine. Several in vivo studies have demonstrated that migraine is associated with metabolic alterations, including impaired energy metabolism, altered glucose utilization, decreased levels of high-energy phosphate intermediates, and increased lactate concentrations. In addition, elevated levels of excitatory neurotransmitters, decreased levels of inhibitory neurotransmitters, increased oxidative stress, and reduced antioxidant levels have been observed in both the brain and blood of animal models with migraine. Clinical studies have also confirmed alterations in metabolomic profiles, with additional evidence of disrupted lipid and amino acid metabolism during both the ictal and interictal phases of migraine. Several interventional studies, including those involving acupuncture, tetramethylpyrazine, Ligusticum chuanxiong, ibuprofen, and triptans, have demonstrated that these interventions can partially reverse these metabolic derangements. Therefore, the present review aims to summarize and discuss findings from both in vivo and clinical studies regarding metabolomics and migraine. Any contradictory findings are also included in this review.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seipin modulates Alzheimer's disease pathogenesis by regulating ferroptosis through a glycine-mediated metabolic pathway.","authors":"Xiaoqiong An, Daoju Wu, Yijia Wang, Zhenkui Ren, Wenfeng Yu","doi":"10.1007/s11011-026-01941-6","DOIUrl":"10.1007/s11011-026-01941-6","url":null,"abstract":"<p><p>Alzheimer's disease (AD) remains an incurable neurodegenerative disorder with an elusive pathogenesis, where emerging evidence implicates metabolic dysregulation and ferroptosis in neuronal loss. Although the BSCL2 gene, which encodes Seipin, is crucial for lipid metabolism, its specific role in the progression of AD remains undefined. This study employed Mendelian randomization (MR) analysis, in vivo APP/PS1 mouse models, and in vitro BV2 microglial assays to elucidate the mechanistic axis linking BSCL2, metabolites, and ferroptosis in AD. MR analysis demonstrated a causal relationship between genetically predicted elevated BSCL2 expression and an increased risk of AD, partially mediated by glycine. Supporting these genetic findings, stereotactic knockdown of Seipin in the hippocampus of APP/PS1 mice significantly ameliorated cognitive deficits without inducing systemic metabolic toxicity. Mechanistically, Seipin deficiency reduced ferroptosis in both AD mouse brains and Aβ-stimulated microglia, as evidenced by the upregulation of anti-ferroptotic markers (GPX4, Nrf2, HO-1) and the suppression of pro-ferroptotic effectors (ACSL4, NCOA4). Moreover, glycine supplementation partially ameliorated the aggravated ferroptotic phenotype caused by Seipin overexpression, indicating a functional feedback mechanism in which glycine facilitates glutathione synthesis to mitigate Seipin-induced lipid peroxidation. These findings collectively identify Seipin as a novel regulator of ferroptosis in the pathogenesis of AD and underscore the potential of the BSCL2-glycine-ferroptosis axis as a therapeutic target. Future research should aim to elucidate the specific molecular interactions between Seipin and the iron-handling machinery and to validate glycine-based interventions in clinical settings as a means to prevent neurodegeneration.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From glycemic control to neuroprotection: alogliptin as a repurposed candidate for Huntington's disease.","authors":"Garima Choudhary, Kanika Vashisht, Varun Sharma, Mahendra Singh Ashawat, Shiv Kumar Kushawaha","doi":"10.1007/s11011-026-01942-5","DOIUrl":"10.1007/s11011-026-01942-5","url":null,"abstract":"<p><p>Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and psychiatric disturbances, for which no disease-modifying therapies are currently available. Emerging evidence implicates metabolic impairment, mitochondrial dysfunction, oxidative stress, and neuroinflammation as central contributors to HD pathogenesis, thereby highlighting novel avenues for therapeutic intervention beyond conventional strategies. In this context, drug repurposing has gained considerable attention as an efficient approach to accelerate therapeutic development. Alogliptin has multiple complementary mechanisms of action that exert neuroprotective effects through inhibition of DPP-4 to boost endogenous incretin signaling (especially GLP-1), inhibition of inflammatory pathways, inhibition of oxidative stress, preservation of mitochondrial function, and modulation of neuronal survival signaling. The review summarizes existing data on the contribution of the incretin signaling to neuroprotection and critically analyzes the mechanism through which alogliptin might regulate important pathological events in HD, such as apoptosis, oxidative stress, and neuroinflammation. Additionally, preclinical results and pharmacological properties in favor of its translational potential are presented, as well as the reflection on its clinical usage and additional research perspectives. Even though direct evidence in HD is not extensive, the overlap of metabolic and neurodegenerative pathways offers a strong argument to study. This review identifies alogliptin as a potent repurposable agent and the necessity to conduct specific experimental and clinical research to determine its effectiveness in refining symptoms and changing the disease course in HD. This narrative review critically evaluates the available experimental evidence supporting the repurposing potential of Alogliptin for HD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural network-enhanced investigation of ferroptosis and druggability in early-onset alzheimer's disease.","authors":"Pratibha Singh, Soumya Lipsa Rath","doi":"10.1007/s11011-026-01939-0","DOIUrl":"10.1007/s11011-026-01939-0","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative disorder which is multifactorial in nature. Some of its characteristics are slow cognitive decline, memory problems and behavioral changes. AD patient brains show a progressive synaptic toxicity, autophagy, neuroinflammation, excess generation of reactive oxygen species (ROS), neuronal death and oxidative stress, which occurs due to disrupted metal homeostasis along with tau and amyloid-β protein deposition. Notably, lipid peroxidation, iron buildup and elevated oxidative stress in AD brains suggest a possible molecular connection between ferroptosis and AD neurodegeneration. This study explores the genetic and bioinformatics perspective on the relationship between ferroptosis and AD aiming to identify potential therapeutic potential biomarkers using Neural network (NN) and Machine learning models. Six ferroptosis related genes were found to be differentially expressed in AD. Further machine learning analysis shortlisted four key biomarker genes. An NN-based diagnostic prediction model was developed and validated using AUC-ROC anaysis, which gave high diagnostic values (AUC- 0.92) in the analysis. The findings highlight a strong correlation between ferroptosis and altered metabolic functions in AD. miRNA-gene interaction analysis revealed that two biomarker genes, CYBB and ACSL4 can be regulated by several regulatory miRNAs i.e., hsa-miR-146-5p, hsa-miR-106b-5p, hsa-miR-223-3p, hsa-miR-155-5p, hsa-miR-34a-5p, hsa-miR-125b-5p and hsa-miR-27a-3p suggesting their potential as early diagnostic potential biomarkers. Immune microenvironment analysis revealed strong neuroinflammatory responses in AD with increased infiltration of macrophages (M0, M1 and M2), monocytes and multiple T cell subsets. This heightened immune activity may be driven by ferroptosis-induced oxidative stress contributing to neuronal death. Furthermore, druggability of these targets was evaluated and several drugs were identified that may be potentially repurposed for therapeutic intervention in AD pathogenesis. This study presents a diagnostic predictive model integrating gene expression, miRNA regulation and immune infiltration analysis, offering a novel perspective on early AD detection. The identified ferroptosis-related potential biomarkers and regulatory miRNAs could serve as valuable tools for clinical diagnosis and targeted therapeutic intervention, advancing personalized treatment strategies for Alzheimer's disease.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between COVID-19 infection, elevated C-reactive protein, and neuropsychiatric symptoms in individuals with metabolic and cardiovascular comorbidities.","authors":"Gabriel S Mondo, Lucas C Pedro, Camila O Arent, Larissa C Pereira, Jéssica L Fernandes, Amanda L Maciel, Luciane B Ceretta, Zuleide Maria Ignácio, Gislaine Zilli Réus","doi":"10.1007/s11011-026-01936-3","DOIUrl":"10.1007/s11011-026-01936-3","url":null,"abstract":"<p><p>Elevated serum inflammatory markers are associated with neuropsychiatric symptoms. This process is potentially more intense in individuals with chronic comorbidities such as obesity, systemic arterial hypertension (SAH), and diabetes mellitus (DM). Such conditions already establish a basal inflammatory state, which can be aggravated by acute viral infections, such as COVID-19, worsening neuropsychiatric outcomes. Given this panorama, this cross-sectional study aimed to analyze the association between the presence of pre-existing comorbidities, elevated plasma C-reactive protein (CRP) levels, and symptoms of stress, anxiety, and depression in individuals previously infected by SARS-CoV-2. The research included 350 participants: 114 in the post-COVID-19 group and 236 in the control group. The post-COVID-19 group had a higher prevalence of comorbidities, notably obesity (17.9%; p = 0.044), DM (13.3%; p < 0.01), and SAH (22.1%; p = 0.024). Furthermore, serum CRP levels were significantly higher in the post-COVID-19 group (p = 0.014) and correlated significantly with all comorbidities. The post-COVID-19 group presented higher stress (p = 0.02) and severity of depressive symptoms (p = 0.034). Specifically, the presence of SAH and obesity was associated with a significant increase in stress levels, depression, and anxiety severity (p = 0.027). In conclusion, the results demonstrate that individuals with pre-existing comorbidities, besides being more prevalent in the post-COVID-19 group, exhibit a higher systemic inflammatory state (high CRP), associated with the exacerbation of neuropsychiatric symptoms.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Exercise-CTSS-AD Axis: a novel framework for understanding exercise-induced neuroprotection in Alzheimer's disease.","authors":"Dong Yang, Wen Guo, Bihan Wang","doi":"10.1007/s11011-026-01930-9","DOIUrl":"10.1007/s11011-026-01930-9","url":null,"abstract":"<p><p>Disease-modifying therapies for Alzheimer's disease (AD) targeting amyloid-β and tau have consistently failed, highlighting the urgent need for innovative therapeutic strategies. Cathepsin S (CTSS), a lysosomal cysteine protease upregulated in AD, functions as a \"multifaceted disruptor\" that interconnects neuroinflammation, blood-brain barrier (BBB) dysfunction, and Aβ metabolic dysregulation. Although exercise is a validated non-pharmacological intervention that mitigates AD pathology, its multi-target molecular mechanisms remain elusive. Here, we propose and substantiate the \"Exercise-CTSS-AD Axis\" hypothesis, positing that exercise confers neuroprotection by suppressing CTSS through synergistic anti-inflammatory, anti-aging, and metabolic regulatory pathways. Exercise-induced myokines and clearance of senescent cells inhibit CTSS transcription, while AMPK-TFEB axis activation enhances lysosomal function to repress CTSS enzymatic activity. This systemic CTSS suppression preserves BBB integrity, ameliorates microglia-driven neuroinflammation, and restores Aβ homeostasis by reducing production and enhancing clearance. Our framework provides a unifying molecular explanation for the pleiotropic benefits of exercise, positions CTSS as a quantifiable biomarker for personalized exercise regimens, and supports an innovative combinatorial strategy: \"Exercise + low-dose CTSS inhibitors\" as a disease-modifying therapy for AD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis.","authors":"Xiaoqin Tan, Yanru Gao, Lingyu Zhang, Yubin He, Qing X Li, Yan Dong","doi":"10.1007/s11011-026-01938-1","DOIUrl":"10.1007/s11011-026-01938-1","url":null,"abstract":"<p><p>Type 2 diabetes-associated cognitive dysfunction (TDACD) is a recognized metabolic brain disorder with limited therapeutic options. This preclinical study investigated whether isoorientin (ISO) confers neuroprotection in TDACD and examined the involvement of the glycogen synthase kinase-3β/nuclear factor erythroid 2-related factor 2 (GSK3β/Nrf2) pathway in its effects. A mouse model of TDACD was induced by high-fat diet and streptozotocin. Mice were administered ISO for six weeks. The systemic metabolism and cognitive behavior were evaluated. The synaptic protein expression, apoptosis, tau phosphorylation, oxidative stress in the brain were detected to identify the pathological signature. The activity of GSK3β and the expression of its downstream targets Nrf2 and heme oxygenase-1 (HO-1) were analyzed to elucidate the mechanism. ISO improved systemic glucose metabolism and alleviated hepatic steatosis, and reversed cognitive deficits. In the brain, ISO restored synaptic proteins (PSD-95, BDNF, soluble α-synuclein), exerted anti-apoptotic effects (increased Bcl-2/Bax ratio, decreased cleaved caspase-3), and attenuated oxidative stress and mitochondrial damage. Mechanistically, ISO inhibited GSK3β activity, promoted Nrf2 nuclear accumulation, upregulated HO-1 expression, and reduced tau phosphorylation at Ser396. These findings demonstrate that ISO exerts a neuroprotective effect in TDACD model by inhibiting oxidative stress via GSK3β/Nrf2 pathway, and highlight ISO as a potential therapeutic candidate for TDACD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MS-based metabolic profiling in serum for bipolar disorder.","authors":"Talha Ağaç, Metin Demirel, Fatmanur Köktaşoğlu, Halime Dulun Ağaç, Şahabettin Selek, Mustafa Solmaz","doi":"10.1007/s11011-026-01932-7","DOIUrl":"10.1007/s11011-026-01932-7","url":null,"abstract":"<p><strong>Background: </strong>Bipolar disorder (BD) is a chronic psychiatric illness characterized by alternating episodes of mania and depression. Diagnostic challenges arise from the subjective nature of clinical assessments, often leading to delayed or inaccurate treatment. The identification of objective biomarkers specific to BD may improve diagnostic accuracy and enable early intervention. This study aimed to analyze serum metabolomic profiles of BD patients during euthymic and manic states to identify potential diagnostic and predictive biomarkers.</p><p><strong>Methods: </strong>Serum samples were collected from 33 patients in the manic phase, 25 patients in the euthymic phase, and 40 healthy controls. Samples were analyzed using high-resolution liquid chromatography-mass spectrometry. Metabolite levels were determined semi-quantitatively. The identified metabolic features were analysed using univariate statistics, confounder-adjusted logistic regression, and multivariate and pathway enrichment approaches.</p><p><strong>Results: </strong>Comparisons between patients with BD and healthy controls revealed alterations primarily in lipid-related metabolites, including primary fatty acid amides, phosphatidylcholine derivatives, and acylcarnitines. Following adjustment, oleamide and 2-arachidonoylglycerol were found to be significantly associated with the euthymic state relative to the control group. In manic patients, several lipid metabolites exhibited consistent directional changes compared to the control group, although most of these associations did not survive multiple testing correction. Direct comparison between the manic and euthymic states identified a limited number of metabolites, suggesting metabolic differences related to the state.</p><p><strong>Conclusion: </strong>This exploratory serum metabolomics study has identified subtle yet biologically plausible metabolic alterations associated with bipolar disorder and its mood states. The findings emphasise the importance of lipid metabolism and mitochondrial energy pathways in the pathophysiology of BD, while also highlighting the influence of mood state. Although the results are preliminary and require validation in larger, longitudinal cohorts that are preferably drug-naïve, they lay the groundwork for future targeted metabolomic studies aimed at clarifying state- and disease-related metabolic signatures in BD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}