Metabolic brain disease最新文献

{"title":"Characterizing the molecular mechanisms underlying aluminium-induced disruptions in neuronal survival pathways.","authors":"Kankipati Sravya, Arpitha Rao, P Harshitha, Aluru Parithathvi, Herman Sunil Dsouza","doi":"10.1007/s11011-026-01953-2","DOIUrl":"10.1007/s11011-026-01953-2","url":null,"abstract":"<p><p>Aluminium, an omnipresent environmental pollutant, has been recognized for its neurotoxic effects, particularly its ability to promote neuronal death. More research evidence links aluminium exposure to death through molecular mechanisms. This review delves into the mechanisms underlying aluminium-induced neurotoxicity, including programmed cell death pathways such as apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis. Aluminium exposure leads to disruption of oxidative homeostasis and induction of endoplasmic reticulum stress, mitochondrial dysfunction and DNA damage, which in turn trigger different cell death pathways. Substantial changes in key signalling pathways, such as the IL-1β/JNK, PI3K/Akt/mTOR, Nrf2/Ho-1, System Xc-/GPX4, and NLRP3 inflammasome activation pathways, were observed. Overall, these intertwined pathways highlight aluminium as a potent modulator of neuronal survival pathways, driving neurodegeneration through multifactorial mechanisms. A thorough understanding of these changes provides a fundamental explanation of the role of aluminium toxicity in the etiology of neurodegenerative diseases and provides a foundation for treatment.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840711","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":"Advanced glycation end products and PTSD: molecular insights and dietary approaches for neuropsychiatric health.","authors":"Km Deeksha, Krishan Kumar Verma, Anjali Saini","doi":"10.1007/s11011-026-01963-0","DOIUrl":"10.1007/s11011-026-01963-0","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Post-Traumatic Stress Disorder is a complex psychiatric condition characterized by persistent fear, emotional dysregulation, cognitive impairment, hyperarousal, and chronic stress. Although PTSD is typically triggered by exposure to traumatic events, the underlying biological mechanisms contributing to its development and progression remain incompletely understood. Glycation, a non-enzymatic biochemical process leading to the formation of Advanced Glycation End Products (AGEs), has emerged as a potential mechanistic link between chronic stress, neuroinflammation, and stress-related neuropsychiatric disorders, including PTSD. This review explores the role of glycation and deglycation in the pathophysiology of PTSD. It examines how chronic psychological stress contributes to AGE accumulation, neuroinflammation, oxidative damage, and neuronal dysfunction. Additionally, the review discusses diagnostic biomarkers, potential therapeutic targets, dietary and nutritional interventions, and hormonal therapies that may help restore glycation-deglycation balance and improve clinical outcomes in individuals with PTSD. A comprehensive review of the literature was conducted to evaluate the molecular and physiological mechanisms underlying PTSD, with particular emphasis on glycation-related pathways. Studies investigating the roles of AGEs, their receptors, endogenous deglycation systems, dietary factors, and pharmacological interventions were analysed. The review also assessed emerging precision medicine approaches and nutritional strategies aimed at reducing AGE formation and mitigating stress-induced neurobiological alterations. Chronic psychological stress may disrupt the physiological balance between glycation and deglycation, leading to carbonyl stress, excessive AGE formation, mitochondrial dysfunction, oxidative stress, and persistent neuroinflammation. AGEs activate the receptor for advanced glycation end products (RAGE), triggering inflammatory signalling pathways such as NF-κB and promoting neuronal injury. Key molecular targets linking PTSD and glycation include RAGE, hypoxia-inducible factor-1 alpha (HIF-1α), KEAP1/Nrf2 signalling, FKBP5-glucocorticoid receptor pathways, the glyoxalase system (GLO1 and GLO2), and DJ-1/PARK7. Biomarker studies reveal alterations across neuroendocrine, inflammatory, genetic, epigenetic, psychophysiological, and neuroanatomical pathways in PTSD. Nutritional interventions rich in polyphenols, antioxidants, omega-3 fatty acids, probiotics, vitamins, and anti-inflammatory compounds may reduce AGE formation, enhance endogenous deglycation mechanisms, and improve neurobiological resilience. Emerging hormonal therapies, including glucocorticoids, DHEA, allopregnanolone, estrogen, testosterone, oxytocin, vasopressin antagonists, and IGF-1 modulation, may further complement conventional PTSD treatment strategies. Dysregulation of glycation and deglycation pathways represents a promising mechanistic framework for underst","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148829152","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":"Vitamin K in brain metabolism and cognitive function: mechanistic evidence, human associations, and unresolved questions.","authors":"Osman Kukula","doi":"10.1007/s11011-026-01962-1","DOIUrl":"10.1007/s11011-026-01962-1","url":null,"abstract":"<p><p>Vitamin K acts as a critical regulator across diverse biological systems, contributing significantly to skeletal integrity, cardiovascular functions, metabolic homeostasis, and immune defenses. Experimental studies increasingly suggest that it also plays an important role in the nervous system, supporting neuronal growth, differentiation, and survival. Its antioxidant, anti-inflammatory, and antiapoptotic effects, along with its capacity to act as an alternative electron carrier in mitochondria, further indicate potential neuroprotective properties. This narrative review synthesizes evidence from recent cell and animal studies, mechanistic research on sphingolipid metabolism, and observational data evaluating vitamin K status and cognitive outcomes. Findings from populations receiving long-term vitamin K antagonist therapy were reviewed to highlight potential clinical implications. Regulation of sphingolipid pathways by vitamin K appears to support neuronal proliferation and resilience, while adequate vitamin K levels have been associated with better cognitive performance. Conversely, prolonged exposure to vitamin K antagonists has been linked to impairments in visual memory and verbal fluency, as well as reductions in brain volume. Evidence also indicates that vitamin K is essential for the synthesis and maintenance of myelin and neuronal membrane components, and for activating vitamin K-dependent proteins that preserve neuronal integrity. Beyond its established role in coagulation, emerging preclinical and observational evidence suggests that vitamin K may possess neuroprotective potential through molecular, structural, and antioxidant mechanisms. The observed association between vitamin K antagonist therapy and cognitive decline in older adults highlights the need for comprehensive clinical studies to clarify causality, determine therapeutic relevance, and better define the role of vitamin K in brain health.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813489","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":"Peripheral metabolic dysfunction is associated with cognitive frailty in a mouse model of type 2 diabetes.","authors":"Maria Teresa Venuti, Federico Brandalise, Mattia Cappelletti, Attilio F Speciani, Michela C Speciani, Erica Cecilia Priori, Francesca Giammello, Elisa Roda, Paola Rossi, Daniela Ratto","doi":"10.1007/s11011-026-01956-z","DOIUrl":"10.1007/s11011-026-01956-z","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder increasingly associated with cognitive impairment and neurodegeneration. Peripheral metabolic dysfunction, particularly insulin resistance and glycation stress, represents a critical link between diabetes and brain pathology. This study investigated the relationship between metabolic alterations and cognitive frailty using a murine T2DM model induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ). Male C57BL/6J mice were longitudinally followed from adulthood to senescence and subjected to HFD alone or HFD plus STZ. Metabolic parameters, including fasting glycemia, oral glucose tolerance, insulin resistance (HOMA-IR), glycated albumin (GA), and methylglyoxal (MGO), were assessed over time. Cognitive function was evaluated using spontaneous behavioral tests of recognition memory (Novel Object Recognition, Object Location, and Y-maze), integrated into a cognitive frailty index. Post-mortem histological and immunohistochemical analyses were performed on pancreatic and hippocampal tissues. While HFD alone induced mild alterations, HFD/STZ mice developed a stable diabetic phenotype with severe hyperglycemia, pancreatic β-cell damage, elevated HOMA-IR, and increased GA and MGO levels. Notably, HFD/STZ mice exhibited a marked decline in recognition memory, affecting both knowledge and remembering components. At the central level, diabetic mice showed hippocampal cytoarchitectural alterations, increased tau hyperphosphorylation, and amyloid accumulation. Crucially, both insulin resistance and glycation stress (GA) directly correlated with recognition memory deficits. These findings demonstrate that peripheral metabolic dysfunction, i.e. insulin resistance and advanced glycation, directly correlates with hippocampal pathology and cognitive decline, supporting the translational relevance of the HFD/STZ model for diabetes-related cognitive frailty.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13498501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795448","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":"Exosome-derived biomarkers as non-invasive tools in stroke, Parkinson's disease, and Alzheimer's disease.","authors":"Athar Talebi, Samira Nabili, Mobarakeh Alaei, Parisa Koohsarian, Ali Doostmohammadi, Mehdi Dadashpour","doi":"10.1007/s11011-026-01947-0","DOIUrl":"10.1007/s11011-026-01947-0","url":null,"abstract":"<p><p>Neurological disorders, including stroke, Parkinson's disease (PD), and Alzheimer's disease (AD), are among the most prevalent and debilitating neuropathological conditions, affecting over 50 million people globally. Effective prevention and treatment strategies require a comprehensive understanding of reliable and disease-specific biomarkers. Such insights can enhance diagnostic precision, enable early detection, and support the development of targeted therapeutic approaches. In this review, we focus on exosome-derived proteins and small non-coding RNAs as promising non-invasive biomarkers for stroke, PD, and AD, given the accessibility and stability of exosomes in biological fluids. Furthermore, we examine their potential diagnostic and therapeutic relevance, emphasizing their functional roles, specificity, and sensitivity. Finally, we discuss current limitations, emerging challenges, and future research directions to guide the advancement of exosome-based biomarker discovery and clinical translation in neurological disorders. However, we emphasize that the comparative effectiveness of exosomal microRNAs (miRNAs) versus protein biomarkers requires direct validation in future head‑to‑head cohort studies.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795465","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":"The potential of vitamins in Huntington's disease: bridging mechanistic evidence with translational limitations and future strategies.","authors":"Vaishnavi Namdeo Padole, Yogesh A Kulkarni","doi":"10.1007/s11011-026-01948-z","DOIUrl":"10.1007/s11011-026-01948-z","url":null,"abstract":"<p><p>Neurodegenerative diseases are characterized by impairment of neuronal functions and neuronal loss. Huntington's disease is one of the neurodegenerative diseases caused by the formation of mutant Huntingtin protein aggregates in the brain. The other pathological reasons behind this disease are oxidative stress, mitochondrial dysfunction, and excitotoxicity, which lead to impairment of motor, cognitive, and psychiatric functions. The vitamins are considered an essential part of a healthy diet, as they tend to increase the nutritional value of the diet. Insufficient intake of macro- and micronutrients can deteriorate human health, which may lead to malnutrition. Nowadays, these vitamins are also considered molecules to manage neurodegenerative disease with the intention of a dual response, along with nourishment. In vivo research reflects the antioxidant potential of vitamins and also functions as an integral part of various metabolic processes of the body that play a vital role in the pathology of Huntington's disease. Despite several neuroprotective properties, current research on vitamins remains limited. The review focuses on evidences exploring the functional significance of vitamins in maintaining neuronal and brain health and their possible impact on the symptoms and pathogenesis of Huntington's disease. It also highlights how the vitamins' potential is at stake to reach the clinical perspective, along with different strategies to overcome their limitations using novel drug delivery and biomarker-based approaches.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795503","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":"Berberine and lactulose combination therapy attenuates neuroinflammation and hepatic injury in thioacetamide-induced hepatic encephalopathy in rats.","authors":"Ashwani Saini, Shreyash Santosh Yadav, Syed Afroz Ali, Ashok Kumar Datusalia","doi":"10.1007/s11011-026-01955-0","DOIUrl":"10.1007/s11011-026-01955-0","url":null,"abstract":"<p><p>Hepatic encephalopathy (HE) represents a severe neuropsychiatric manifestation secondary to advanced hepatic dysfunction, predominantly driven by hyperammonaemia and associated neuroinflammatory processes. Although lactulose remains a mainstay in the clinical management of HE due to its ammonia-lowering properties, its limited efficacy in attenuating neuroinflammation necessitates the use of adjunctive therapeutic strategies. Previously, we identified berberine, a plant-derived isoquinoline alkaloid, as an anti-HE agent via the reduction of neuroinflammation and NLRP3 inflammasome activation. Therefore, in the present study, we investigated the potential beneficial effects of co-administering berberine and lactulose in a rat model of thioacetamide (TAA)-induced hepatic encephalopathy. HE was induced via intraperitoneal injections of TAA (200 mg/kg) on alternate days for one week. Animals received oral pre-treatment with lactulose (8 mL/kg) alone or in combination with berberine (100 mg/kg) for 14 consecutive days. Comprehensive behavioural assessments were conducted alongside biochemical quantification of systemic ammonia, hepatic transaminases (ALT, AST), and oxidative stress markers (MDA, GSH) in both hepatic and cerebral tissues. Histopathological evaluations of the liver and brain further corroborated the biochemical findings. Notably, combination therapy significantly ameliorated cognitive deficits, reduced systemic ammonia burden, normalised liver and brain enzyme profiles, and markedly attenuated central neuroinflammatory signalling, as evidenced by reduced hippocampal NF-κB activation and GFAP immunoreactivity, in addition to suppressing hepatic NF-κB expression, surpassing the effects observed with monotherapy. Histological analyses revealed reduced neuronal degeneration and hepatic architectural disruption. These findings underscore the therapeutic potential of berberine-lactulose co-treatment in mitigating both hepatic and neuroinflammatory pathologies associated with HE, offering a promising adjunctive strategy for improving neurocognitive outcomes in liver failure.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795459","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":"Chiglitazar alleviates cognitive dysfunction in diabetic mice by restoring mitochondrial function via the PPARs/Nrf2 signaling pathway.","authors":"Junfang Yuan, Yuzhong Wang, Defeng Wang, Yanfeng Zhen, Yanan Sun, Li Wang, Hui Fang","doi":"10.1007/s11011-026-01951-4","DOIUrl":"10.1007/s11011-026-01951-4","url":null,"abstract":"<p><strong>Background: </strong>Diabetes is a chronic metabolic disorder associated with hyperglycemia, which often leads to cognitive dysfunction and mitochondrial impairment. Chiglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist. However, the precise mechanism through which Chiglitazar alleviates cognitive dysfunction in diabetic mice remains unclear.</p><p><strong>Methods: </strong>A diabetic mouse model was established through intraperitoneal injection of streptozotocin (STZ), and high-glucose-induced neuronal injury model. The Morris water maze assessed spatial memory. HE and Nissl staining evaluated cortical and hippocampal structural changes. Western blot measured PPARs, Nrf2, and TFAM protein levels. mtDNA, ATP, SOD, and MDA levels were analyzed, and mitochondrial ultrastructure was assessed via transmission electron microscopy (TEM).</p><p><strong>Results: </strong>Diabetic mice exhibited hyperglycemia and cognitive impairment, with longer escape latencies and reduced time in the target quadrant. HE and Nissl staining showed neuronal loss and structural damage, which Chiglitazar ameliorated. mtDNA, ATP, and SOD levels decreased, while MDA increased in diabetic mice and the high-glucose-induced neuronal injury model, Chiglitazar ameliorated this phenomenon. Western blot results showed that Chiglitazar increased the protein expression levels of PPARα, PPARγ, PPARδ, Nrf2 and TFAM. TEM revealed severe mitochondrial damage in high-glucose conditions. Chiglitazar treatment alleviated these ultrastructural abnormalities.</p><p><strong>Conclusion: </strong>Chiglitazar regulates the PPARs/Nrf2 pathway and reverses mitochondrial dysfunction to improve cognitive function in diabetic mice.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795506","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":"Hesperidin attenuates aluminum chloride-induced cognitive impairment by modulating ERK/MAPK Signaling, tau protein immunoexpression, neuroinflammation, and microglial activation in mice.","authors":"Rademene Sunday Oria, Kingsley Ekpe Akpang, Runyi Bassey Ben, Vivian Oluoma Aneke, Imasa Emmanuel Ushie, Maduka Jennifer Uchenna, Gift Bartsunkefe Ikong, Jesam Ibor Uket, Confidence Woko, Omamuyovwi Meashack Ijomone","doi":"10.1007/s11011-026-01933-6","DOIUrl":"10.1007/s11011-026-01933-6","url":null,"abstract":"<p><p>Aluminum chloride (AlCl₃) is widely used to model Alzheimer's-related neurotoxicity and cognitive decline. Hesperidin, a citrus flavanone with antioxidant and anti-inflammatory properties, has unclear neuroprotective mechanisms against aluminum-induced neurodegeneration. This study investigated hesperidin's neuroprotective effects against AlCl₃-induced cognitive impairment in mice, focusing on ERK/MAPK signaling, tau expression, neuroinflammation, and microglial activation. Mice received AlCl₃ (100 mg/kg) daily for four weeks, hesperidin (100 mg/kg), both, or vehicle, with hesperidin administered during weeks 3 and 4 in the co-treated group. Cognitive function was assessed using the Morris water maze and Y-maze tests. TNF-α and IL-1β were quantified in brain tissue. IBA1-positive microglial density, ERK immunoreactivity, and tau expression were evaluated immunohistochemically in the hippocampal CA3 region and the prefrontal cortex. AlCl₃ impaired spatial and working memory, elevated pro-inflammatory cytokines, increased microglial activation, and upregulated ERK and tau immunoexpression in both regions. Hesperidin co-treatment significantly rescued cognitive deficits, attenuated neuroinflammation, reduced microglial reactivity, modulated ERK signaling, and decreased tau overexpression. These findings demonstrate that hesperidin protects against AlCl₃-induced neurodegeneration by concurrently modulating neuroinflammatory and kinase-dependent pathways, supporting its therapeutic potential in aluminum-related tauopathies.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795493","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":"Peripheral nerve injury induces an immunometabolic signature involving reduced free fatty-acid pools.","authors":"Jun Seo Park, Hye Won Jun, Jaesung Lee, Sung Joong Lee","doi":"10.1007/s11011-026-01927-4","DOIUrl":"https://doi.org/10.1007/s11011-026-01927-4","url":null,"abstract":"<p><p>Peripheral nerve injury-induced persistent pain hypersensitivity cannot be fully explained by increased neuronal excitability alone. Rather, it is increasingly recognized as a pathological tissue state characterized by sustained glial activation, immune signaling, and synaptic remodeling within the spinal cord. In this context, metabolic remodeling of the spinal cord has emerged as a potentially important feature of neuropathic pain. However, the metabolic patterns associated with this state, and their relationship to underlying molecular programs, remain incompletely defined. Here, we performed GC-MS-based untargeted metabolomic profiling of the spinal cord dorsal horn on day 7 after spinal nerve transection (SNT). To provide orthogonal validation, we integrated pathway-analysis results from four independent spinal cord RNA-sequencing datasets derived from distinct neuropathic pain models and further conducted qPCR-based validation. Metabolic profiling revealed a clear separation between SNT and sham samples, marked by broad depletion of the free fatty acid pool and features consistent with an immunometabolic shift. Consistently, analyses across RNA-sequencing datasets and qPCR validation demonstrated upregulation of immune and inflammatory programs, together with downregulation of fatty acid metabolism and cholesterol homeostasis. Collectively, these findings suggest that persistent neuropathic pain should be interpreted not simply as a consequence of neuronal and immune signaling, but also through the metabolic tissue environment that supports and sustains this pathological state.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13481569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795474","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}