Journal of Neurochemistry最新文献

{"title":"Unconventional Protein Secretion in the Central Nervous System: Mechanisms and Roles in Physiology and Disease.","authors":"Steven A Krauklis, Sevnur Kömürlü Keçeli, Edward M Campbell, Prabhodh S Abbineni","doi":"10.1111/jnc.70532","DOIUrl":"10.1111/jnc.70532","url":null,"abstract":"<p><p>Extracellular secretion of neurotransmitters, proteins, and peptides by cells of the central nervous system underpins neurological function and homeostasis. Decades of elegant research have illuminated the molecular mechanisms and machinery that support the release of neurotransmitters via synaptic vesicle exocytosis, as well as the secretion of signal-peptide bearing proteins through the endoplasmic reticulum (ER)-Golgi based secretory pathways. However, it is now increasingly appreciated that signal-peptide lacking \"leaderless\" proteins can also be secreted via ER-Golgi-independent mechanisms collectively termed unconventional protein secretion (UcPS). In this review, we highlight the physiological and pathological consequences of UcPS in the central nervous system. UcPS supports the secretion of aggregation-prone proteins such as α-synuclein and mutant huntingtin, pro-inflammatory mediators including interleukin-1β and high mobility group box protein 1, and neuroprotective or angiogenic factors such as fibroblast growth factor 2. Furthermore, several retroelement-derived proteins, encoded by ancient genomic elements with structural homology to retroviruses, are also secreted via unconventional pathways, and are thought to regulate essential CNS processes such as synaptic plasticity. These diverse cargoes underscore the functional range of UcPS in neuronal and glial biology. We summarize current understanding of the major UcPS pathways used by CNS cells. These mechanisms include plasma-membrane pore-mediated release facilitated by proteins such as gasdermin-D, as well as vesicular routes in which UcPS cargoes enter organelles of the autophagic and endolysosomal systems that subsequently fuse with the plasma membrane to enable extracellular release. Finally, we discuss key unresolved questionRecent evidence from HeLa cells suggests regarding the regulation of UcPS, including the molecular features that target select leaderless cargoes toward UcPS, how the balance between conventional secretion and UcPS shifts under cellular stress, and the current understanding of the diverse molecular machinery that mediates the vesicular form of UcPS.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":"e70532"},"PeriodicalIF":4.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148592265","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":"Limitations and Strengths of the SH-SY5Y Neuroblastoma Cell Line as a Model of β-Amyloid Neurotoxicity: Lessons From a Systematic Review and Meta-Analysis.","authors":"Nathalia R Pinheiro, Clarissa F D Carneiro, Giulia S Cancelliero, Giovanna O Nogueira, Glaucia M Almeida, Nathalia Fernandes, Ana Paula Wasilewska-Sampaio, Samantha M Martins, Antonio Felix, Olavo B Amaral, Adriano Sebollela","doi":"10.1111/jnc.70523","DOIUrl":"10.1111/jnc.70523","url":null,"abstract":"<p><p>The SH-SY5Y human neuroblastoma cell line is widely used as an in vitro model of β-amyloid (Aβ) neurotoxicity in Alzheimer's disease (AD). However, the lack of standardized protocols for assessing Aβ toxicity-including differentiation strategies for SH-SY5Y cells-limits the comparability of results across studies. To address these issues, we conducted a systematic review and meta-analysis to evaluate how methodological factors influence Aβ-induced toxicity in SH-SY5Y cells. We included 359 eligible studies encompassing 1192 MTT-based comparisons of cell viability between Aβ-treated and control SH-SY5Y cells. A three-level meta-analysis estimated mean cell viability after Aβ exposure at 63% of control levels (95% CI [61.6; 64.3]), with very high heterogeneity (I² = 99.6%). Meta-regression identified significant associations between increased toxicity and higher Aβ concentrations, longer exposure durations, and the use of peptide preparations described as fibrils. Conversely, differentiation protocols, duration, and cell density did not significantly influence toxicity outcomes. Reporting quality was often poor, with frequent omissions regarding cell line origin, authentication, contamination testing, Aβ preparation details, and nature of the experimental unit. Overall, our findings show robust Aβ toxicity in SH-SY5Y cells, primarily driven by dose, exposure time, and Aβ aggregation state, but not cell differentiation status. Our conclusions highlight the critical need for better reporting of Aβ exposure parameters to enhance reproducibility and translational potential in AD research.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":"e70523"},"PeriodicalIF":4.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579063","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":"APP/Aβ Signaling Orchestrates Reactive Astrocyte Networks in Alzheimer's Disease.","authors":"Gretsen Velezmoro Jauregui, Sophie Coomes, Elizabeth Emmett, Alex Thatcher, Nicole Oyelakin, Maria Čarna, Jana Zelinkova, Jan Sebastian Novotny, Natalie Polakova, Tarun Kuruvilla, Robert Zorec, Alexei Verkhratsky, Vladimir Parpura, David Morgan, Kenneth L Moya, Clara Limback-Stokin, Gorazd Bernard Stokin","doi":"10.1111/jnc.70526","DOIUrl":"10.1111/jnc.70526","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neurofibrillary pathology, synaptic dysfunction, and chronic neuroinflammation, yet the mechanisms driving early, localized pathology remain elusive. While traditionally viewed through a neuron-centric lens, astrocytes express abundant amyloid precursor protein (APP)-predominantly Kunitz-type protease inhibitor (KPI)-containing isoforms-and possess the complete enzymatic machinery for APP processing and Aβ clearance. Astrocytic APP is a stress-responsive signaling molecule regulated by inflammatory, metabolic, excitotoxic, and mechanical insults. Under local tissue stress, reactive astrocytes upregulate APP and shift toward amyloidogenic processing. The resulting bioactive fragments, including Aβ, promote astrocyte activation, disrupt homeostatic functions, and trigger feed-forward upregulation of endogenous APP. We propose that this reciprocal coupling establishes a self-reinforcing network where APP integrates local stress and diffusible Aβ propagates reactive states across the astroglial syncytium. This framework positions astrocytic APP signaling as an upstream driver of localized amyloid accumulation, neuroinflammation, and sporadic AD progression.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":"e70526"},"PeriodicalIF":4.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579088","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":"Is Nuclear mTOR Relevant for Neuronal Dysfunction?","authors":"Shiwani Kumari, Roberto Pagano, Katarzyna Orzol, Jacek Jaworski","doi":"10.1111/jnc.70528","DOIUrl":"10.1111/jnc.70528","url":null,"abstract":"<p><p>The mammalian target of rapamycin (mTOR) is a key regulator of neuronal development, metabolism, and plasticity, and its dysregulation is linked to many neurological disorders. Most studies have focused on cytoplasmic mTOR, yet mTOR is also present in the nucleus. In non-neuronal cells, nuclear mTOR has been linked to transcription, chromatin organization, and RNA metabolism. In neurons, its role remains largely unknown. Here, we present a focused Perspective on nuclear mTOR in the nervous system. We briefly summarize the best-established nuclear functions of mTOR, drawing mainly on evidence from non-neuronal cells. We then reanalyze published mTOR interactome datasets to assess whether these mechanisms may be relevant to neurons. Repeated links were observed to nuclear processes, particularly transcription, chromatin regulation, RNA processing, and DNA repair. Similar patterns were observed for gene sets associated with neurodevelopmental and neurodegenerative disorders. However, these associations are correlative and do not establish causality. Based on these findings, we propose a set of testable predictions and experimental approaches to directly examine nuclear mTOR function in neurons, including selective perturbation of its nuclear activity and analysis of gene expression and RNA processing. A key open question is whether nuclear mTOR has a functional role in neurons beyond its well-established cytoplasmic activities. This Perspective summarizes current evidence, highlights key gaps, and outlines directions for future studies on nuclear mTOR in neuronal function and disease.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":"e70528"},"PeriodicalIF":4.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536090","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":"Neurobiological and Behavioral Consequences of Prenatal Methadone or Buprenorphine Exposure: Insight From Animal Models","authors":"Henriette Nyberg,&nbsp;Jannike Mørch Andersen","doi":"10.1111/jnc.70499","DOIUrl":"https://doi.org/10.1111/jnc.70499","url":null,"abstract":"<p>The marked increase in opioid use over the past three decades has been accompanied by increased use of medications for opioid use disorder (MOUD), including during pregnancy. However, methadone and buprenorphine, the primary MOUDs, cross the placenta and the immature fetal blood–brain barrier, raising concerns about potential effects on offspring development. In this review, we summarize experimental animal studies published over the past 25 years examining neurobiological and behavioral outcomes following prenatal exposure to methadone or buprenorphine. Although animal models cannot fully establish human outcomes, they offer important insights into causal relationships and underlying biological mechanisms that are difficult to study in clinical populations. Our aims were to compare the effects of methadone and buprenorphine, assess sex-specific and intergenerational effects, and identify areas where further preclinical research is needed. In total, 53 studies were identified. Collectively, the findings show that prenatal MOUD exposure is associated with alterations in several key neurobiological processes, including opioid receptor expression and signaling, neurotransmitter systems, neurotrophic pathways, neurogenesis and neuronal maturation, synaptic organization and plasticity, myelination, structural development, and neuroinflammation. Behavioral outcomes include alterations in cognitive function, affective and social behaviors, reward-related behavior, and pain sensitivity. Evidence for sex-specific and intergenerational effects is increasing, but the overall evidence base remains limited. Substantial variability in findings limits the ability to draw definitive conclusions. Future studies should integrate mechanistic and functional approaches and focus on comparisons between methadone and buprenorphine, sex-specific differences, and intergenerational effects using translationally relevant models. More knowledge is crucial for supporting evidence-based decision-making during pregnancy and for minimizing potential long-term risks to offspring.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70499","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148358021","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":"Norepinephrine Couples Astrocytic Metabolism to mTOR-Driven Protein Synthesis","authors":"Florencia Cabrera-Cabrera,&nbsp;Helena Tull,&nbsp;Giulia Urone,&nbsp;Age Utt,&nbsp;Maria Kuhtinskaja,&nbsp;Robert Zorec,&nbsp;Indrek Koppel","doi":"10.1111/jnc.70507","DOIUrl":"https://doi.org/10.1111/jnc.70507","url":null,"abstract":"<div>\u0000 \u0000 <p>Norepinephrine is a neuromodulator that regulates diverse physiological processes in the central nervous system, including astrocytic metabolism. While its metabolic actions in astrocytes are well characterised, its role in regulating protein synthesis remains unknown. Here, we show that norepinephrine robustly stimulates protein synthesis in rat primary cortical astrocytes in a time-dependent manner, comparable to that of insulin and serum. This effect is mediated predominantly by β-adrenergic receptors and is accompanied by activation of the mTOR–S6K signalling pathway. We further demonstrate that this translational response requires glycolytic activity and is preceded by a rapid depletion of astrocytic glycogen stores and a transient reduction in ATP levels. Together with growth factors, these findings identify protein synthesis as a previously unrecognised physiological target of norepinephrine in astrocytes and reveal a mechanism linking neuromodulatory signalling, metabolic state and mTOR-dependent translational control in the brain.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148358176","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":"Preface to the Special Issue “Astrocytes in Cognition and Behavior”","authors":"João Filipe Oliveira,&nbsp;Alfonso Araque","doi":"10.1111/jnc.70501","DOIUrl":"10.1111/jnc.70501","url":null,"abstract":"<p>Astrocytes, once viewed as passive support cells in the central nervous system, are now recognized as active and dynamic regulators of neural function. Across multiple domains of central nervous system function, astrocytes interact closely with neurons to influence synaptic transmission, plasticity, and behavior. These include key brain and spinal cord functions related to information processing that impact cognition and animal behavior. This Special Issue features 12 comprehensive reviews and original data articles that highlight key advances and ongoing challenges in this field. These works collectively reflect a major shift from a neuron-centered perspective to an integrated neuron–glia framework, in which astrocytes sense neuronal and neuromodulator activity and actively shape neural circuit function in health and disease contexts.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352269","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":"Astrocytic Regulation of Aberrant Perineuronal Net Formation in Mecp2-Null Neocortex","authors":"Ashis Sinha,&nbsp;Angelica M. Kowalchuk,&nbsp;Nasim Khatibi,&nbsp;Russell T. Matthews,&nbsp;Jessica L. MacDonald","doi":"10.1111/jnc.70503","DOIUrl":"10.1111/jnc.70503","url":null,"abstract":"<p>Rett syndrome (RTT), caused by mutations in <i>MECP2</i>, is a complex neurological disorder characterized by myriad physiological disruptions, including early closure of the critical period of developmental plasticity and precocious formation of perineuronal nets (PNNs). PNNs are lattice-like substructures of extracellular matrix (ECM) that enwrap specific subpopulations of neurons. PNNs are essential in the modulation of neuronal plasticity and brain maturation, and their enzymatic disruption can partially restore plasticity in adults and improve memory. Although precocious PNN formation is well-established in RTT, little is known of the cellular, molecular, or biochemical underpinnings of their precocious formation, or whether precocious PNN formation is due to cell-autonomous or non-cell-autonomous mechanisms. While PNNs form on subsets of neurons throughout the brain, astrocytes secrete many ECM components that form PNNs, and they play a central role in controlling closure of the critical period. We find that <i>Mecp2</i>-null mouse astrocyte conditioned media induces the expression of the key PNN component <i>Hapln1</i> and causes enhanced PNN formation on wildtype mouse neurons in vitro, suggesting that <i>Mecp2</i>-null astrocytes play a key role in the precocious formation of PNNs in RTT. Further, we identify increased expression of HAPLN1 and other PNN/ECM components in the developing mouse <i>Mecp2</i>-null cortex, and demonstrate that PNNs are structurally and biochemically mature at an earlier developmental stage. These results provide essential insight into the mechanisms and structure of aberrant PNNs in <i>Mecp2</i>-null cortex and identify potential new avenues for targeted rescue or reversal of the precocious closing of the critical period in RTT.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70503","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352155","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":"Comparison of Proteomic Analysis of Cerebrospinal Fluid From Neurological Patients With and Without Amyotrophic Lateral Sclerosis","authors":"Eleonora Sabetta,&nbsp;Karin Rallmann,&nbsp;Pille Taba,&nbsp;Abigail L. Pfaff,&nbsp;Bal Hari Poudel,&nbsp;Davide Ferrari,&nbsp;Massimo Locatelli,&nbsp;Sulev Kõks,&nbsp;Jonas Bergquist","doi":"10.1111/jnc.70508","DOIUrl":"https://doi.org/10.1111/jnc.70508","url":null,"abstract":"<p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symptoms. Approximately 85% of ALS cases are sporadic (sALS), while the remaining 10%–15% are familial (fALS). Biological biomarkers of sporadic ALS remain poorly understood, hindering precise patient screening, delaying diagnosis and negatively affecting prognosis. This study aims to identify potential proteomic biomarkers by comparing the cerebrospinal fluid (CSF) of sALS patients with that of patients suffering from other neurological diseases. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) was used for proteomic profiling of CSF samples from 24 sALS patients and 26 patients with other neurological diseases. The complete protein expression profiles were compared using a two-tailed Student's <i>t</i>-test, with a <i>p</i> &lt; 0.05 considered statistically significant with additional FDR correction at the 0.1 level. Proteomic analysis of CSF samples identified significant quantitative changes in 96 proteins with threshold <i>p</i> &lt; 0.05 and 74 proteins with FDR &lt; 0.1 between sALS and non-ALS patients, including alterations in proteins associated with neurodegenerative processes, such as amyloid precursor proteins and inflammatory markers. CSF proteomic analysis reveals altered inflammatory and neurodegenerative metabolic pathways, providing valuable insights into the proteomic landscape of sALS. Several dysregulated proteins were consistent with the disease mechanisms highlighted in previous studies. These findings represent a step forward in developing personalised approaches for diagnosing and managing the disease.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324709","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":"Kynurenine Pathway Metabolite Levels in Drug Naïve and Risperidone Treated Schizophrenia: Insights From Systemic and Post-Mortem Brain Tissue Analysis","authors":"Joyappa Nikhil,&nbsp;Chinnasamy Thirumoorthy,&nbsp;Priyamvada Sharma,&nbsp;Vijay Kumar,&nbsp;Shivarama Varambally,&nbsp;Kuppan Gokulakrishnan","doi":"10.1111/jnc.70504","DOIUrl":"10.1111/jnc.70504","url":null,"abstract":"<div>\u0000 \u0000 <p>Kynurenine pathway (KP), the principal route of tryptophan (TRY) metabolism, is implicated in schizophrenia (SCZ), but findings remain inconsistent, particularly regarding peripheral-central associations and links to immune dysregulation. We measured KP metabolites, cytokines, and metabolic risk factors in serum from drug-naïve (DN) and risperidone-treated (RT) SCZ patients versus healthy controls (HC) as well as in post-mortem brain tissue from an independent cohort by assessing KP metabolites, enzyme expression (mRNA, protein) and cytokine profiles. We recruited a total of 227 participants from the clinical services of a large neuropsychiatric hospital, which included DN SCZ (<i>n</i> = 66), RT SCZ (<i>n</i> = 87), and HC (<i>n</i> = 74). Additionally, brain KP metabolite levels and the mRNA and protein expression of key enzymes and cytokines were evaluated in the dorsolateral prefrontal cortex (DLPFC) samples from the post-mortem cohort of 10 SCZ patients and 17 controls. KP metabolites were measured using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Both DN and RT groups exhibited significantly reduced TRY (<i>p</i> &lt; 0.05), elevated kynurenine (KYN), kynurenic acid (KYNA), KYN/TRY ratio and serotonin (SER) in serum (<i>p</i> &lt; 0.001), alongside higher TNF-α, and IFN-γ and lower IL-10 (<i>p</i> &lt; 0.001 for both). These alterations were correlated with metabolic risk factors, symptom severity of SCZ, and immune markers, and these remained associated with disease status after adjusting for confounders. Post-mortem analyses confirmed increased brain KYN (<i>p</i> &lt; 0.05) and KYNA (<i>p</i> &lt; 0.001) in the DLPFC of SCZ, accompanied by upregulation of Tryptophan 2,3-dioxygenase (TDO2) (<i>p</i> &lt; 0.001) and Kynurenine aminotransferase II (KAT II) (<i>p</i> &lt; 0.05) expression and elevated pro-inflammatory cytokines. Our findings provide convergent evidence for KP dysregulation in SCZ, linking immune activation with enhanced change toward KYNA synthesis both systemically and centrally. The observed alterations across independent serum and post-mortem brain cohorts support the potential relevance of these molecular signatures to SCZ pathophysiology and their possible therapeutic implications.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308432","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}