Search Results (1,231)

Background and Objectives: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and current therapies provide only limited symptomatic relief without effectively slowing its progression. Increasing evidence suggests that aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade contributes to AD-associated neuroinflammation. This study investigated the therapeutic potential and molecular mechanisms of JAK inhibitors in AD using integrated bioinformatics and network pharmacology approaches. Materials and Methods: Potential anti-AD targets of JAK inhibitors were identified using the SwissTargetPrediction and GeneCards databases. Functional enrichment, protein–protein interaction (PPI) analysis, transcriptomic validation using public datasets, regulatory network construction, molecular docking, normal mode analysis (NMA), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction were performed to investigate the potential mechanisms of action of these drugs in AD. Results: Our analysis identified 163 shared targets between JAK inhibitors and AD. Enrichment analysis revealed that these genes were primarily involved in protein phosphorylation and were enriched in key signaling pathways, including the neurotrophin, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling pathways. PPI analysis identified AKT1, BCL2, SRC, STAT3, and TNF as five highly ranked hub targets across multiple topological algorithms. Transcriptomic validation confirmed significantly higher expression of these targets in the prefrontal cortex of individuals with AD compared with normal subjects. Molecular docking indicated that pacritinib and momelotinib showed relatively favorable predicted interactions with the hub proteins, while NMA revealed differences in the predicted flexibility of the docked complexes. Furthermore, ADMET prediction showed that pacritinib possesses favorable pharmacokinetic properties for the treatment of AD. Conclusions: Collectively, these findings provide mechanistic insights into the potential effects of JAK inhibitors in AD and identify pacritinib as a computationally prioritized candidate that warrants experimental validation in appropriate AD models. However, as this study is based solely on computational analyses without wet-lab validation, the findings should be considered hypothesis-generating in silico evidence, and the potential safety concerns of pacritinib require further investigation. Full article

Fractional ionizing radiation (FIR) is a standard cancer therapy but often induces severe central nervous system complications, including cognitive decline and physiological dysfunction. While natural flavonoids hold therapeutic promise for radiation-induced brain injury (RIBI), optimizing their combinations and elucidating the underlying molecular pathways remain challenging. Methods: To develop a precise therapeutic strategy, we first integrated network pharmacology and UHPLC-Q-Orbitrap MS/MS analysis to identify three highly effective flavonoid monomers from a radioprotective botanical extract. Subsequently, an in vivo anti-inflammatory screening was conducted to determine the optimal combinatorial ratio, designated as the ternary formulation QLI. The neuroprotective efficacy of QLI was then systematically evaluated in a mouse model of fractional RIBI (cumulative dose of 12 Gy) through behavioral assessments, hematopoietic profiling, and neurotransmitter analyses. Transcriptomic alterations were explored via RNA-sequencing (RNA-seq) and validated by molecular docking, RT-qPCR, and Western blotting. Results: Pharmacological and mass spectrometry analyses identified Quercetin, Luteolin, and Isorhamnetin-3-O-glucoside as the core bioactive monomers. Quantitative synergistic screening established the optimal QLI formulation at a mass ratio of 2:1:1. In vivo, FIR exposure induced severe spatial memory deficits, disrupted neurotransmitter homeostasis, and caused hematopoietic decline. Administration of QLI successfully reversed these physiological and cognitive impairments. Transcriptomic profiling revealed that QLI globally reprogrammed aberrant gene expression, specifically normalizing signaling networks related to the PI3K–Akt pathway, apoptosis, and neuroactive ligand–receptor interactions. Multidimensional validation confirmed that QLI mitigated neuroinflammation, suppressed astrocyte hyperactivation (GFAP), and preserved synaptic plasticity by preventing the pathological accumulation of SynGAP and autophagic stress (Beclin-1). Conclusions: The rationally designed ternary flavonoid formulation (QLI) provides potent neuroprotection against fractional RIBI. By resolving neuroinflammation, alleviating synaptic plasticity suppression, and normalizing stress-induced transcriptomic disruptions, QLI represents a promising multi-target experimental formulation with the potential to mitigate radiotherapy-associated neurological side effects. Full article

Background: The dynamic advancement of pediatric hemato-oncology and intensified therapeutic protocols have significantly increased survival rates while simultaneously highlighting the challenge of long-term treatment complications. Within the cohort of adolescent and young adult (AYA) survivors, delayed neurocognitive deficits, often manifesting as the chemobrain phenotype, and psychosocial disorders constitute a particularly substantial burden. Contemporary neurogastroenterological evidence indicates a fundamental role of persistent dysbiosis and gut–brain axis dysfunction in the pathogenesis of these alterations. This review aims to critically synthesize translational evidence elucidating the impact of iatrogenic gut microbiota damage and modifiable dietary patterns on the development of long-term neurocognitive sequelae in survivors of early childhood cancer. Methods: A systematized narrative review was conducted in accordance with the SANRA guidelines by integrating data from in vivo models and observational studies. A comprehensive literature search across the PubMed, Embase, Cochrane Central, Scopus, and Web of Science databases up to June 2026 was performed utilizing the Population, Exposure, and Outcomes (PEO) framework. Results: Oncological therapies, including myeloablative conditioning and broad-spectrum antibiotic therapy, induce a microbial scar phenomenon characterized by the depletion of commensal Firmicutes in favor of resistant pathobionts. The subsequent decline in the synthesis of neuroprotective short-chain fatty acids (SCFAs) alongside the pathological activation of the kynurenine pathway disrupts central nervous system homeostasis. Translocation of lipopolysaccharides (LPSs) across the compromised intestinal barrier generates systemic inflammation recognized as inflammaging, which, in turn, stimulates neurotoxic microglial hyperreactivity. This pathophysiological cascade is accelerated by a pro-inflammatory Western diet, whereas anti-inflammatory interventions such as the MIND diet and postbiotics demonstrate measurable restorative potential. Conclusions: The pathophysiology of delayed neurotoxicity is largely a consequence of systemic neuroinflammation driven by intestinal dysbiosis. Implementing individualized dietary and microbiome-targeted strategies into survivorship care protocols constitutes a crucial direction for clinical prophylaxis. Validating their clinical efficacy in the AYA population necessitates prospective randomized controlled trials integrated with shotgun metagenomic sequencing. Full article

Epidemiological and clinical evidence indicates that obesity-associated metabolic dysfunction increases the risk of depression, which is often resistant to conventional antidepressant therapies. Elucidating targeted mechanisms underlying obesity-related depression is therefore essential for developing effective interventions. Accumulating evidence identifies neuroinflammation as a central link between obesity and depressive disorders. Obesity-driven inflammatory signaling disrupts multiple neurobiological processes implicated in depression, thereby contributing to the onset and progression of inflammatory depression. Polyphenols, a diverse class of plant-derived secondary metabolites, have demonstrated neuroprotective properties, attributed to their anti-inflammatory, antioxidant, and metabolic regulatory effects. By restoring neurobiological homeostasis, polyphenols may represent a promising therapeutic strategy for obesity-related inflammatory depression. This review summarizes the pathophysiological mechanisms through which obesity induces neuroinflammation and subsequently promotes depressive symptoms. It further evaluates current evidence regarding the efficacy and effective dosing of polyphenols in attenuating inflammatory signaling and alleviating obesity-related inflammatory depression, as well as the translational challenges faced in their clinical application. Given their anti-neuroinflammatory potential, polyphenols may serve as a valuable adjunctive approach for the management of obesity-related inflammatory depression. Full article

Background/Objectives: The aim of the present study was to investigate the mechanisms in Parkinson’s disease (PD), a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, aggregation of α-synuclein, mitochondrial dysfunction, oxidative stress, neuroinflammation, gut dysbiosis, and blood–brain barrier (BBB) impairment. Although there are several approved therapies that have been developed, their aqueous solubility, oral bioavailability, first-pass metabolism, and inability to penetrate the BBB make them less effective over time. This review is intended to critically analyze the potential of self-nanoemulsifying drug delivery systems (SNEDDSs) as a pathogenesis-related approach to enhance the delivery and therapeutic activity of repurposed drugs and conventional drugs for PD. Methods: A comprehensive literature search was conducted to address the pathogenic mechanisms of PD, the deficiencies of current pharmacotherapy, recent developments in SNEDDS formulation strategies and their application in improving oral bioavailability, lymphatic transport, BBB penetration and targeted brain delivery. A special focus was dedicated to drug repurposing, functionalized SNEDDSs, PEGylation, and gut–brain axis modulation. Results: SNEDDSs significantly enhance the water solubility, stability, intestinal absorption and systemic exposure of poorly water-soluble therapeutic agents and, to a certain extent, lymphatic uptake to avoid first-pass metabolism. These systems include improved brain delivery, decreased pharmacokinetic variability, and prolonged drug levels within the therapeutic range. Moreover, SNEDDSs can be used to deliver multiple molecules that are found to be neuroprotective, antioxidant, anti-inflammatory and probiotic, all at once, which can act on multiple pathogenic mechanisms associated with PD. Functionalized and PEGylated SNEDDSs add further to formulation stability, extend systemic circulation and increase efficiency of brain targeting. Conclusions: SNEDDSs are a promising translational nanomedicine platform for enhancing the effectiveness of conventional and repurposed therapeutics in PD, which address key pharmacokinetic and biological challenges. The next generation of oral therapies with targeted surface engineering, precision drug repurposing and clinical validation will be expected to bring about a faster advancement of drugs that can alter the course of disease rather than giving only symptomatic relief. Full article

Neurodegenerative conditions are incurable, progressive disorders characterized by the slow and irreversible loss of neurons. This neuronal loss can lead to several neuropsychiatric disorders and long-term complications. Despite significant advances in understanding the mechanisms of neurodegenerative disease, currently, there is no cure for neurodegenerative diseases, highlighting the urgent need for novel neuroprotective strategies. Alkaloids are an important class of bioactive substances that exhibit neuroprotection against several neurodegenerative diseases. Tryptanthrin, an indoloquinazoline alkaloid, shows strong anti-inflammatory, antioxidant, and neuroprotective properties. In this review, we described the pathophysiology of neurodegenerative diseases and summarized several alkaloids’ neuroprotective properties. Furthermore, we showed protective benefits of tryptanthrin and its derivatives against neurodegenerative illnesses, focusing on their modulation of oxidative stress, neuroinflammation, neuronal death, and related signaling pathways in cellular and animal models of neurodegenerative diseases. However, various challenges, such as clinical evidence, pharmacokinetic studies, and long-term treatment effects, are not well documented. Future research on tryptanthrin and its derivatives should focus on the optimization of drug delivery methodologies and clinical studies to establish its potential as a therapeutic candidate for neurodegenerative diseases. Full article

Neuroinflammation plays a central role in Alzheimer’s disease (AD). Glycyrrhizin (GL), a major component of licorice, exhibits anti-inflammatory effects, but its effects on AD pathology remain unclear. To investigate the effects of GL (18β-glycyrrhizin, 18β-GL) and its stereoisomer (18α-glycyrrhizin, 18α-GL) on cognitive function, neuroinflammation, and AD pathology in senescence-accelerated mouse prone 8 (SAMP8; P8) mice, 40-week-old P8 male mice, an AD model due to aging, and the control (senescence-accelerated mouse resistant 1, SAMR1; R1) mice were treated with 18β-GL, 18α-GL and physiological saline (control) for 12 weeks (n = 6 in each group). Cognitive function was evaluated using a step-through passive avoidance test. Plasma levels of α-Klotho, IGF-1, 2′,3′-cyclic GMP-AMP (2′,3′-cGAMP), HMGB1, IL-6, and TNF-α were measured by ELISA. Hippocampal microglial activation (Iba1), amyloid-β (Aβ) deposition, and phosphorylated tau (p-Tau) were assessed by immunohistochemistry. Aged P8 mice showed impaired memory, decreased α-Klotho and IGF-1 levels, and increased inflammatory markers compared with R1 mice. GL significantly improved memory performance, reduced inflammatory markers, and suppressed Iba1 activation, as well as Aβ and p-Tau accumulation. These effects were associated with inhibition of the cGAS–STING pathway, as indicated by reduced 2′,3′-cGAMP and HMGB1 levels. GL ameliorates AD pathology by inhibiting neuroinflammation, suggesting its therapeutic potential for AD. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder involving metabolic impairment, neuroinflammation, synaptic failure, and comorbidities. Hence, therapeutic development for AD is rapidly shifting from a single-target approach, centred on amyloid-beta (Aβ) reduction, to multi-target strategies. In this study, we investigated the neuroprotective profile of two acetanilide derivatives, SG-22 and SG-23, originated from the halogen-free thyronamine-like lead compound SG-2. Their efficacy was evaluated through an integrated approach combining in vitro cellular models, in vivo phenotypic screening in a Caenorhabditis elegans AD model, and comprehensive ADME-Tox profiling. In U87MG cells, both SG-22 and SG-23 effectively prevented Aβ_25–35-induced cytotoxicity and restored autophagy-related gene expression, including LC3, SIRT1, and SIRT6, while reducing mTOR and SIRT5 levels. Furthermore, all compounds exhibited anti-inflammatory effects in activated HMC3 microglial cells, reducing IL-6 and increasing IL-10 levels, with evidence suggesting partial involvement of TAAR1 signalling. ADME-Tox analyses revealed improved safety and metabolic profiles for the tested compounds, particularly SG-22, which showed reduced hERG liability and enhanced cytochrome P450 stability. However, in vivo studies demonstrated that only SG-2 and SG-23 improved motility and fitness in the C. elegans AD model, consistent with their ability to activate autophagy, whereas SG-22 was ineffective due to limited organismal uptake. Ultimately, the monoacetylated analogue SG-23 emerges as a promising candidate, balancing neuroprotective efficacy and drug-like properties, and supporting thyronamine-like analogues as multi-target agents for AD. Full article

Chronic stress is increasingly recognized as a major contributor to systemic disease. Prolonged or repeated activation of the hypothalamic–pituitary–adrenal (HPA) axis and sympathoadrenal systems may contribute to glucocorticoid receptor resistance and chronic low-grade inflammation, although stress-related responses vary depending on stressor characteristics, population, age, sex, health status, and study design. Elevated levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), oxidative stress, and NF-κB activation contribute to immune dysfunction, neuroinflammation, metabolic disturbances, reproductive and endocrine imbalance, as well as structural and functional alterations in stress-sensitive brain regions. Prolonged exposure to stress may contribute to the development of neuropsychiatric, cardiovascular, metabolic, neurodegenerative, and malignant diseases, highlighting the need for effective strategies to mitigate the detrimental consequences of chronic stress. Given the limitations and adverse effects associated with conventional pharmacological approaches, increasing attention has been directed toward natural bioactive compounds. Terpenes represent a diverse class of phytochemicals with reported anti-inflammatory, antioxidant, and neuromodulatory properties. Terpenes such as limonene and β-caryophyllene, as well as terpenoids such as linalool, may modulate NF-κB, MAPK, and Nrf2 signaling pathways and interact with the endocannabinoid system, thereby attenuating neuroinflammation, oxidative stress, and stress-induced immune dysregulation. This review summarizes current evidence regarding the mechanisms linking chronic stress, HPA axis dysfunction, and systemic disease, with particular emphasis on endocrine, immune, and nervous system alterations. In addition, it critically evaluates the mechanistic and translational potential of terpenes as possible indirect neuroimmune and redox modulators of stress-related pathophysiology. Full article

Background/Objectives: Neuroinflammation is increasingly recognized as a key mechanism linking infectious diseases with psychiatric disorders through interactions between peripheral immune activation, metabolic pathways, and brain network alterations. This review aimed to synthesize current evidence on the neuroimmune mechanisms and biomarkers underlying infection-associated psychiatric disorders. Methods: A narrative literature review structured according to the SANRA (Scale for the Assessment of Narrative Review Articles) criteria was conducted using the Web of Science Core Collection, PubMed/MEDLINE, Scopus and PsycINFO databases. Boolean search strategies identified studies investigating neuroinflammatory biomarkers, neuroimmune mechanisms, and psychiatric outcomes associated with infectious diseases. The search (January 2022–30 June 2026) included 76 studies in the final qualitative analyses. Results: The reviewed evidence consistently identified inflammatory cytokines and chemokines, complement proteins, blood–brain barrier markers, glial activation biomarkers, neuroaxonal injury markers, kynurenine pathway metabolites, neurotrophic factors, and neuroimaging markers as complementary indicators of infection-induced neuroimmune dysfunction. Across diverse bacterial, viral, parasitic, and systemic infections, these mechanisms converged on peripheral immune activation, blood–brain barrier disruption, microglial activation, kynurenine pathway dysregulation, impaired neurotrophic signaling, synaptic dysfunction, and altered brain network connectivity, contributing to depression, anxiety, psychosis, cognitive impairment, and fatigue. Based on these findings, a unified neuroimmune model integrating peripheral and central mechanisms is proposed. Conclusions: Neuroinflammation emerges as a shared biological pathway linking infections with transdiagnostic psychiatric phenotypes. Although no single biomarker currently demonstrates sufficient diagnostic specificity, integrated multimodal biomarker panels may improve biological stratification, facilitate earlier identification of high-risk patients, and support the development of mechanism-based precision approaches—including candidate anti-inflammatory pharmacological strategies currently under clinical investigation—for infection-associated psychiatric disorders. Full article

Introduction. In recent years, cannabidiol (CBD) has been used as an adjunct therapy to anti-seizure medications for the control of seizures in patients with drug-resistant epilepsy. In addition to its anticonvulsant effect, CBD also has well-defined anti-inflammatory properties. Since neuroinflammation can trigger various pro-epileptogenic mechanisms, CBD could play an inhibitory role in this process. Epileptogenesis is the process by which epilepsy becomes a chronic disease following a brain injury, and one of its main characteristics is an increased susceptibility to seizures due to a reduced seizure threshold. However, the role of CBD in modulating this susceptibility remains poorly understood. Methodology. We developed an experimental protocol to discretely measure the seizure threshold (DMST) 7 or 14 days after lithium-pilocarpine-induced status epilepticus (SE) through the administration of small intraperitoneal (i.p.) doses of pentylenetetrazol (15 mg/kg/every 10 min). Results. Using the DMST, we observed a significant decrease in the seizure threshold after SE associated with a hypersensitivity state characterized by irritability and marked weight loss. A separate cohort of rats was treated with CBD (20 mg/kg) for 14 days following SE. Conclusions. Treatment with CBD did not improve the seizure threshold; moreover, it worsened the hypersensitivity state and delayed recovery following SE. Our results suggest that orally administered CBD, at a human-equivalent therapeutic and safe dose, does not improve susceptibility to seizure development after SE. Full article

Autism spectrum disorder (ASD) and epilepsy are complex, frequently co-occurring neurodevelopmental and neurological disorders that share key mechanisms, such as altered neurotransmission, oxidative stress, neuroinflammation, and gut–brain axis disruption. Despite pharmacological advances, current treatments often provide only partial relief and are associated with significant side effects. The comorbidity of ASD and epilepsy, affecting millions worldwide, remains under-recognised and poorly addressed, imposing a profound burden on patients, families, and healthcare systems through reduced quality of life, increased caregiving demands, and substantial social and economic costs. This review highlights the convergent pathways shared between ASD and epilepsy, including immune dysregulation, synaptic dysfunction, and metabolic imbalance, which create opportunities for unified therapeutic strategies. Marine algae have emerged as a sustainable source of bioactive compounds offering a unique potential to address these overlapping pathologies. Algal polyunsaturated fatty acids, carotenoids, polyphenols, polysaccharides, and vitamins have antioxidant, anti-inflammatory, neuroprotective, and microbiota-modulating activities. By addressing both the biological underpinnings and clinical burden of ASD–epilepsy comorbidity, algae-based strategies represent a novel and ecologically sustainable direction for mitigating ASD–epilepsy comorbidity and advancing marine-inspired neurotherapeutics. Full article

Within the emerging field of nutritional neuroscience, omega-3 fatty acids are among the most extensively investigated dietary bioactive compounds with potential relevance to cognitive aging. As populations continue to age worldwide, identifying modifiable nutritional factors that support cognitive health has become an important public health priority. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), obtained primarily from marine sources, are integral components of neuronal membranes and serve as precursors of specialized pro-resolving lipid mediators. This narrative review integrates concepts from nutritional neuroscience and geroscience to examine how dietary omega-3 fatty acids may influence biological pathways involved in age-related cognitive decline. Current evidence suggests that DHA and EPA affect multiple processes linked to brain aging, including neuroinflammation, synaptic plasticity, mitochondrial function, oxidative stress, cerebrovascular integrity, cellular senescence, and gut–brain axis signaling. These mechanisms overlap with several hallmarks of aging and may contribute to the maintenance of cognitive function during later life. Observational studies generally associate higher dietary intake or circulating omega-3 status with better cognitive performance and a lower risk of cognitive decline and dementia. Findings from randomized controlled trials are less consistent, although benefits appear more likely in individuals with low baseline omega-3 status, mild cognitive impairment, or increased biological vulnerability. Beyond their established anti-inflammatory effects, omega-3 fatty acids may influence multiple aging-related pathways, particularly inflammaging, vascular aging, and mitochondrial dysfunction. Although heterogeneity in study design, dosage, intervention timing, and participant characteristics precludes firm conclusions, viewing omega-3 fatty acids through a geroscience lens offers a useful framework for interpreting existing evidence and informing future research. Overall, omega-3 fatty acids represent a promising nutritional strategy for supporting cognitive health across the lifespan, warranting further investigation in well-characterized populations and precision nutrition approaches. Full article

Background and Clinical Significance: Encephalitis is a rare neurological complication associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. In rare cases, focal neuroinflammation can manifest as a mass-like parenchymal lesion, creating profound diagnostic and treatment dilemmas by mimicking primary central nervous system neoplasms. Case Presentation: A 34-year-old female presented with cephalalgia, nausea, confusion, facial palsy, and a new onset of focal impaired awareness seizures (FIAS). Brain magnetic resonance imaging (MRI) revealed a prominent hyperintense lesion within the left temporal lobe with associated vasogenic edema and focal leptomeningeal enhancement highly suspicious of a low-grade glial neoplasm. Although nasopharyngeal RT-PCT was negative, the presence of serum anti-SARS-CoV-2 IgM and IgG suggested recent subclinical SARS-CoV-2 infection. To resolve diagnostic ambiguity and avoid empiric oncological overtreatment, a stereotactic brain biopsy was performed. Histopathology revealed acute neuroinflammation characterized by reactive gliosis, microglial hyperplasia, and perivascular lymphatic cuffing, with no evidence of neoplastic presence. Quantitative tissue RT-PCR confirmed the presence of SARS-CoV-2 (Ct33). Follow-up imaging demonstrated complete resolution of the abnormalities following conservative treatment with corticosteroids and antiepileptics, though mild clinical symptoms persisted for 12 months thereafter. Conclusions: Encephalitis presents a rare yet critical manifestation of SARS-CoV-2. Establishing definitive etiology remains challenging. Stereotactic biopsy is a valuable tool to guide appropriate treatment in cases of ambiguous imaging and clinical findings. Radiographic resolution may precede complete clinical recovery. Full article

Background: Chronic insomnia (CI) is increasingly recognized to be closely associated with neuroimmune dysregulation and neuroinflammation. While the dietary flavonoid quercetin exhibits known broad-spectrum anti-inflammatory properties, its specific multi-target network and underlying mechanisms concerning CI-associated neuroinflammation remain systematically unmapped. Therefore, this study integrated network pharmacology with in vitro experimental validation to elucidate the specific targets and mechanistic pathways of quercetin against neuroinflammatory responses implicated in CI. Methods: Potential targets of quercetin were predicted using the SwissTargetPrediction and SEA platforms, while CI-associated targets were curated from GeneCards, OMIM, and CTD. To bridge computational predictions with physiological relevance, protein–protein interaction (PPI) and functional enrichment analyses were integrated with molecular docking to assess the binding landscape of key candidates. Subsequently, to empirically validate these network-derived mechanistic hypotheses, in vitro experiments were conducted using an LPS-stimulated BV2 microglial model. Pro-inflammatory mediators were quantified via qRT-PCR, and the regulatory dynamics of the RAGE/NF-κB axis were evaluated by Western blotting. Results: Fifty-five overlapping targets were identified, prioritizing six hub genes (e.g., TNF, AKT1, IL6). By harmonizing the predicted network topology with experimental observations in the BV2 microglial framework, our results provide a unified mechanism linking quercetin to the suppression of central neuroinflammation. Enrichment highlighted the AGE-RAGE and IL-17 pathways as central mechanistic nodes. Molecular docking confirmed high-strength affinities between Quercetin and core targets. In the in vitro neuroinflammation model, quercetin (10, 30, and 60 μM) exerted a dose-responsive suppression of TNF-α, IL-1β, IL-6, and iNOS, while concurrently elevating anti-inflammatory IL-10 levels. Mechanistically, Quercetin significantly downregulated RAGE expression and blunted the phosphorylation of P65 and IκB, leading to significant reductions in p-P65/P65 and p-IκB/IκB ratios. Conclusions: Our findings demonstrate that Quercetin may attenuate neuroinflammatory responses associated with CI through modulation of the RAGE/NF-κB signaling axis, as indicated by network pharmacology prediction and further supported by validation in an LPS-stimulated BV2 microglial model. While these in vitro anti-inflammatory effects provide a robust mechanistic basis for targeting neuroimmune dysregulation, further in vivo behavioral studies are necessary to evaluate its direct therapeutic efficacy against chronic insomnia. Full article