Nuclear factor-κB as a key inflammatory mediator in psychiatric diseases: A narrative review

Abstract

Nuclear factor-κB (NF-κB) is a central transcription factor that links peripheral immune activation to neuroinflammatory responses in the brain, playing a key role in the pathophysiology of several psychiatric disorders. This review examines the aberrant activation of NF-κB in major depressive disorders, schizophrenia, post-traumatic stress disorder, bipolar disorder, and autism spectrum disorder. It delves into the cell-type-specific mechanisms through which NF-κB modulates neuroinflammation, synaptic plasticity, and neuronal function in microglia, astrocytes, and neurons, and explore its interactions with other key pathways, such as nuclear factor erythroid 2-related factor 2, hypoxia-inducible factor 1-alpha, and NOD-like receptor family pyrin domain containing 3. Furthermore, we summarize current indirect and direct therapeutic strategies targeting NF-κB signaling and discuss the potential of biomarker-guided personalized medicine.

Key Words: Nuclear factor-κB; Psychiatric diseases; Neuroinflammation; Microglia; Astrocytes; Synaptic plasticity; Immune dysregulation

Core Tip: Nuclear factor-κB (NF-κB) is a central transcription factor linking peripheral immune dysregulation to neuroinflammation in psychiatric disorders. It exerts cell-type-specific effects on microglia, astrocytes, and neurons, interacting with nuclear factor erythroid 2-related factor 2, hypoxia-inducible factor 1-alpha, and NOD-like receptor family pyrin domain containing 3 pathways. Targeting NF-κB and its regulators offers promising therapeutic potential for personalized psychiatry.

INTRODUCTION

Psychiatric diseases are a major contributor to global disability and disease burden; however, their underlying pathophysiological mechanisms remain complex and not completely elucidated[1,2]. Research indicates that factors, such as immune dysregulation and chronic low-grade inflammation, play critical roles in their etiology[3-5]. Nuclear factor-κB (NF-κB), a central transcription factor, serves as a pivotal nexus linking peripheral immune activation to central neuroinflammatory responses and broadly regulates cellular stress, inflammatory gene expression, and synaptic plasticity[6-8]. Recent studies have revealed abnormal activation of the NF-κB signaling pathway across several psychiatric disorders[9-12]. This activation is not only present in peripheral immune cells but also prominently observed in key brain regions. It is intricately associated with elevated levels of pro-inflammatory cytokines, enhanced reactivity of microglia/astrocytes, and impaired neuronal function[13-15]. NF-κB profoundly influences emotions, cognition, and social behavior by regulating diverse mechanisms such as neuroinflammation, oxidative stress, metabolic reprogramming, and epigenetic modifications[16,17]. This review focuses on major depressive disorder (MDD), schizophrenia, post-traumatic stress disorder (PTSD), bipolar disorder (BD), and autism spectrum disorder (ASD). These disorders represent a spectrum of psychiatric conditions—mood disorders, psychotic disorders, trauma-related disorders, and neurodevelopmental disorders. We aim to provide a comprehensive overview of the aberrant activation patterns of NF-κB across different psychiatric disorders and the supporting evidence, to provide an in-depth analysis of the specific molecular and cellular mechanisms through which NF-κB drives pathological processes within different brain cell types, and to explore its crosstalk with other key signaling pathways. Furthermore, the article will summarize current indirect and direct therapeutic strategies targeting NF-κB and discuss prospects for personalized medicine based on NF-κB-associated biomarkers. This narrative review is based on a comprehensive literature search (PubMed, Web of Science; up to January 2026) using keywords related to NF-κB and each psychiatric disorder.

NF-κB ACTIVATION IN PSYCHIATRIC DISORDERS

MDD

NF-κB signaling is consistently implicated in the pathophysiology of MDD[18,19]. Increased nuclear translocation of NF-κB has been observed in immune cells of patients with MDD, alongside elevated activity in post-mortem brain regions such as the prefrontal cortex and hippocampus[20]. This heightened NF-κB activity strongly correlates with elevated levels of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)[21,22]. Preclinical studies confirm a causal role, demonstrating that inhibiting NF-κB produces antidepressant-like effects in animal models[23,24]. For example, 12-[[(tricyclo[3.3.1.1^3:7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid, the sEH inhibitor, regulates the arachidonic acid/NF-κB pathway to suppress inflammatory responses in the prefrontal lobes of rats with postpartum depression-like symptoms, mitigating PPD-like behaviors[25]. Adiponectin, an adipokine, has emerged as a potential mediator in the anti-inflammatory effects observed in MDD[26]. Notably, mechanisms such as exercise can alleviate depressive symptoms by boosting adiponectin, which crosses the blood-brain barrier to inhibit hippocampal NF-κB and shift microglia toward an anti-inflammatory state[27]. Recent transcriptomic data further demonstrated that this pathway is overactive in immune cells of unmedicated patients with MDD, with part of the signal linked to cytomegalovirus reactivation[28,29]. Meta-analyses identify a clinically relevant inflamed subgroup, with roughly 27% of patients with MDD exhibiting elevated C-reactive protein (CRP) levels associated with greater symptom severity and treatment resistance[30,31].

Schizophrenia

Dysregulated NF-κB signaling is associated with neuroinflammation in schizophrenia[32]. Preclinical studies highlight microglial NF-κB in disease pathology. Increased hippocampal p65 levels have been demonstrated to correlate with neuroinflammation and behavioral deficits in an MK-801-induced mouse model, both reversed by dietary α-linolenic acid (ALA), which binds microglial G protein-coupled receptor 120 (GPR120), recruits β-arrestin2, and inhibits the TAK1/NF-κB/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) axis[16]. In humans, a distinct pattern of NF-κB dysregulation is observed in peripheral leukocytes. Although NF-κB-activating receptors (TLR4 and TNFR2) and RelB are elevated, mRNA levels of key kinases, IKKβ and NIK, are reduced, particularly in a “high-inflammation” subgroup with elevated CRP and IL-1β. This kinase downregulation may sustain peripheral inflammation by impairing negative feedback, suggesting a schizophrenia-specific regulatory imbalance[33]. In addition, altered expression of NF-κB-associated long non-coding RNAs (lncRNA) has been detected in the blood of patients, providing further evidence of immune dysregulation and suggesting potential peripheral biomarkers for the disorder[34]. Further supporting the relevance of peripheral measures, a study of monocytes found that the effect sizes of differentially expressed genes displayed a moderate correlation with those in postmortem brain tissue from patients with schizophrenia, indicating that peripheral immune cells may partially reflect central immune-transcriptional alterations[35].

PTSD

PTSD is a severe neuropsychiatric condition characterized by persistent symptoms such as re-experiencing traumatic events, heightened anxiety, and hyperarousal. Research implicates neuroinflammation and immune dysregulation as key contributors to its pathophysiology[36-38]. Central to this inflammatory response is the NF-κB signaling pathway, which plays a critical role in the aberrant consolidation and retrieval of fear memories that underlie PTSD[39,40]. Preclinical models demonstrate that long-term hippocampal NF-κB activation correlates with persistent PTSD-like behaviors, which can be reduced by NF-κB inhibition[41]. NF-κB activity is required for memory reconsolidation—the process by which retrieved memories become labile and are re-stabilized—in the basolateral amygdala (BLA). Inhibiting NF-κB in the BLA disrupts reconsolidation, underscoring its potential as a therapeutic target for weakening maladaptive fear memories in PTSD[40,42,43]. Clinically, patients with PTSD report an upregulation of NF-κB target genes in monocytes, indicating altered peripheral inflammatory pathways[44]. This systemic dysregulation is associated with elevated pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, which can cross the blood-brain barrier, activate microglia, and disrupt synaptic plasticity in regions such as the amygdala[45]. Such microglial activation and neuroinflammation have been directly linked to the dysregulation of fear memory in PTSD[46,47].

Overview of other disorders

NF-κB signaling plays a significant role in the pathophysiology of multiple neuropsychiatric disorders, notably BD and ASD, primarily through its involvement in immune-inflammatory processes, oxidative stress, and neuroinflammation. NF-κB activity in BD is hypothesized to fluctuate dynamically across manic and depressive episodes, interacting with processes such as oxidative stress and mitochondrial dysfunction[48,49]. Recent research has demonstrated a significant upregulation of the NF-κB-associated lncRNA CHAST in the peripheral blood mononuclear cells of patients with BD, particularly in females[48]. Furthermore, other NF-κB-related lncRNAs, such as DILC and DICER1-AS1, exhibit gender-specific dysregulation patterns in BD, further implicating NF-κB pathway anomalies in the immune-inflammatory mechanisms of the disorder[5]. ASD has been intricately linked to maternal immune activation (MIA) and early-life neuroinflammation[50,51]. Peripheral blood analyses in children with ASD reveal significant upregulation of several NF-κB-associated lncRNAs, such as ANRIL, NKILA, ADINR, DILC, and CHAST[52]. In addition, preclinical evidence from an IUGR rat model further underscores the critical role of NF-κB, demonstrating that its dysregulated activation in hippocampal microglia, mediated by disrupted AHR signaling, contributes directly to aberrant synaptic pruning and the manifestation of ASD-like behaviors[53]. NF-κB p65 has been identified as a key regulator of IL-6 expression in the prelimbic cortex of ASD model mice, and its inhibition can alleviate social deficits[16] (Table 1).

Table 1 Clinical and preclinical evidence of nuclear factor-κB dysregulation across psychiatric disorders.

Disorder	Human findings	Preclinical models	Proposed core mechanisms
MDD	Tissue/cell type: PBMCs, post-mortem PFC and hippocampus. NF-κB metric: ↑ Nuclear translocation, ↑ p65 activation. Direction: Positive correlation with IL-6, TNF-α levels[20-22]	AUDA (sEH inhibitor), adiponectin, exercise[23-25,27]	NF-κB-driven neuroinflammation, microglial activation, cytokine release
Schizophrenia	Tissue/cell type: Peripheral leukocytes, post-mortem brain. NF-κB metric: ↑ TLR4/TNFR2, ↑ RelB; ↓ IKKβ/NIK mRNA. Direction: Complex dysregulation with kinase downregulation[33,35]	MK-801-induced model, ALA supplementation[16]	Microglial NF-κB/NLRP3 activation, immune-transcriptional dysregulation
PTSD	Tissue/cell type: Monocytes, PBMCs. NF-κB metric: ↑ NF-κB target gene expression. Direction: Associated with ↑ IL-1β, IL-6, TNF-α[44,45]	Fear conditioning models, NF-κB inhibition in BLA[40-42]	NF-κB-dependent fear memory reconsolidation, microglial priming
BD	Tissue/cell type: PBMCs. NF-κB metric: ↑ NF-κB-associated lncRNA CHAST (particularly in females)[48]. Direction: Gender-specific dysregulation patterns[5,49]	In vitro models of oxidative stress	NF-κB activity fluctuates with manic/depressive episodes; interacts with oxidative stress and mitochondrial dysfunction
ASD	Tissue/cell type: Peripheral blood. NF-κB metric: ↑ Multiple NF-κB-associated lncRNAs (ANRIL, NKILA, CHAST)[52]. Direction: Upregulation correlated with immune activation	IUGR rat model, AHR–NF-κB signaling[16,53]	Microglial synaptic pruning, NF-κB/IL-6 axis in social behavior deficits

TNF-α: Tumor necrosis factor-alpha; MDD: Major depressive disorder; PTSD: Post-traumatic stress disorder; BD: Bipolar disorder; ASD: Autism spectrum disorder; PBMCs: Peripheral blood mononuclear cells; PFC: Prefrontal cortex; AUDA: 12-[[(tricyclo[3.3.1.13:7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid; ALA: Α-linolenic acid; BLA: Basolateral amygdala; IUGR: Intrauterine growth restriction; lncRNA: Long non-coding RNA; IL-6: Interleukin-6; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; NF-κB: Nuclear factor-κB.

Molecular and cellular mechanisms

Synthesizing the evidence across psychiatric disorders, we propose a two-part conceptual framework for understanding NF-κB’s role. First, NF-κB serves as a convergent molecular hub where diverse etiological factors—genetic vulnerability, psychological stress, infection, circadian disruption, and gut dysbiosis—converge to initiate neuroinflammation. Second, this initial activation drives a temporal cascade: Microglial priming and pro-inflammatory polarization (NF-κB-dependent) → astrocytic dysfunction and reactive states → synaptic impairment and neuronal dysfunction in key brain circuits (prefrontal cortex, hippocampus, amygdala). This cascade ultimately manifests as disorder-specific symptoms depending on the brain regions and developmental timing involved.

NF-κB in microglia: Microglia, the resident macrophages of the brain, exhibit a pro-inflammatory (M1-like) phenotype upon activation through TLR or cytokine receptor signaling, with the transcription factor NF-κB serving as a central convergence point[54]. This phenotypic shift is intricately linked to metabolic reprogramming, transitioning from oxidative phosphorylation to aerobic glycolysis, a process co-regulated by NF-κB, hypoxia-inducible factor 1-alpha (HIF-1α), and mTOR[55-57]. This metabolic alteration fuels the sustained production of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, along with ROS and NO, all of which directly contribute to neuronal damage and synaptic dysfunction[58]. Spatial transcriptomics has revealed context-specific heterogeneity in microglial NF-κB activation. Studies in neurodegenerative models demonstrate that distinct microglial subpopulations exhibit NF-κB-enriched transcriptional profiles depending on the pathological stimulus[59-62]. This principle of context-dependent NF-κB engagement is highly relevant to psychiatric disorders, where localized neuroinflammation in specific brain subregions may drive distinct symptom dimensions[63]. Upstream regulators of NF-κB activation extend beyond traditional pathways. For instance, microglial lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) activates NF-κB through the p38-MAPK pathway in hypoxic–ischemic conditions, thereby driving the production of cytokines and ROS that cause neuronal damage[64]. Furthermore, the expression of LOX-1 itself is sustained by a positive feedback loop involving NF-κB and HIF-1α, exacerbating the inflammatory response[50,64]. In addition, epigenetic regulation significantly modulates NF-κB-driven inflammation. The downregulation of the epigenetic regulator polycomb group ring finger 1 (PCGF1) in microglia in models of adolescent depression l derepresses the pro-inflammatory gene matrix metalloproteinase-10 (MMP10)[23]. Normally, PCGF1 recruits repressive histone markers to the MMP10 promoter via RING1B and EZH2. Its loss results in MMP10 upregulation, which subsequently activates NF-κB and MAPK pathways, promoting the release of cytokines (IL-1β and TNF-α) and contributing to depressive-like behaviors[65]. Conversely, inhibitory pathways exist that can mitigate NF-κB-driven neuroinflammation. In the context of schizophrenia pathology, the activation of microglial GPR120 by ALA promotes β-arrestin2 recruitment[16]. This interaction interferes with TAK1, inhibiting both NF-κB and the NLRP3 inflammasome, which ultimately fosters an anti-inflammatory phenotype in microglia[66]. Furthermore, inhibiting the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 in an LPS-induced neuroinflammation model reduced NF-κB activation, diminished pro-inflammatory markers, such as cyclooxygenase-2 and IL-1β, and attenuated overall microglial activation[58]. This finding confirms that aerobic glycolysis is a critical sustainer of NF-κB responses and represents a viable therapeutic target for several neuroinflammatory conditions[57].

NF-κB in astrocytes: NF-κB activation in astrocytes can impair their crucial homeostatic functions, disrupting processes such as glutamate uptake and altering glycolysis and TCA cycle activity, thereby impacting cellular energetics and redox balance. This dysfunction is implicated in several neuropsychiatric and neurodegenerative conditions[67-69]. A landmark CRISPR interference screen conducted in human iPSC-derived astrocytes has revealed that the synergistic action of pro-inflammatory cytokines, specifically IL-1α, TNF, and complement component 1q, induces two distinct inflammatory reactive astrocyte signatures (IRAS) via canonical NF-κB activation[70]. These signatures, IRAS1 and IRAS2, are regulated by autocrine–paracrine feedback loops[71]. IRAS1 is characterized as an “IL-1/IL-6-responsive” state and is notably marked by the upregulation of complement component 3[72,73]. Conversely, IRAS2 represents a “TNF/IFN-responsive” state and is distinguished by the expression of vascular cell adhesion molecule 1[70]. The transcription factor, STAT3, plays a complex, context-dependent regulatory role in these reactive states, promoting the IRAS1 phenotype while simultaneously inhibiting the IRAS2 state. This highlights that NF-κB activation in astrocytes does not elicit a monolithic response but rather diverse, pathology-associated reactive states with potentially distinct functional outcomes, moving beyond a simplistic view of astrocytes merely losing homeostasis[74]. Reactive astrocyte subpopulations are not uniformly distributed but cluster in pathology-affected brain regions, this spatial resolution moves beyond the binary view of astrocyte activation, highlighting how local microenvironments finely tune astrocyte states[75].

NF-κB in neurons: NF-κB plays a dual role in neurons in either promoting neuronal survival or inducing apoptosis, depending on the specific stimuli and cellular context[76,77]. Its activation in neurons is triggered by the key neurotransmitter glutamate through two major signaling pathways: One involving metabotropic glutamate receptors and epidermal growth factor receptor cascades, which regulate cell survival and proliferation, and the other via direct NMDAR-mediated calcium influx[78-80]. This activation is influenced by different stimuli, including neurotrophic factors during development, which induce genes involved in cell differentiation and survival, and excitatory synaptic activity in the mature nervous system[81,82]. Redox-sensitive pathways, notably NF-κB and the antioxidant factor nuclear factor erythroid 2-related factor 2 (Nrf2), often function in opposition to regulate neuronal survival and apoptosis[83]. Although NF-κB is expressed in neurons, its activity can be relatively low; some studies indicate that it displays limited activation in telencephalic neurons compared to its robust activity in glial cells[84,85].

Cross-talk with other transcription factors: Inflammatory cytokines, which are often upregulated through NF-κB signaling, can significantly inhibit the proliferation and differentiation of NSCs in the hippocampal DG[86]. NF-κB activation in brain endothelial cells upregulates adhesion molecules, including VCAM-1 and ICAM-1, which increases blood-brain barrier (BBB) permeability[87]. This allows enhanced infiltration of peripheral immune cells and inflammatory mediators into the brain, creating a vicious cycle that perpetuates neuroinflammation. The Nrf2 and NF-κB signaling pathways exhibit a dynamic, reciprocal relationship. Nrf2 activation suppresses NF-κB activity and associated inflammation, whereas excessive NF-κB activation, common in chronic inflammation, can inhibit the protective functions of Nrf2[88]. This disruption of the Nrf2–NF-κB balance is a key mechanism driving the neuroinflammation and oxidative damage observed in several psychiatric disorders[83]. Interventions such as Dl-3-n-butylphthalide demonstrate therapeutic potential by concurrently modulating both pathways[89]. Beyond direct immune signaling, NF-κB mediates the gut-brain axis by translating microbial signals into neuroinflammation[90]. Short-chain fatty acids like butyrate cross the BBB and suppress microglial NF-κB via two mechanisms: Inhibiting histone deacetylases to silence pro-inflammatory gene promoters, and activating GPR109A receptors to block NF-κB activation[91,92]. Preclinical studies confirm that probiotic supplementation attenuates neuroinflammation and improves behavioral outcomes in psychiatric disease models by inhibiting the NF-κB pathway in the hippocampus and prefrontal cortex[93]. This positions the gut microbiota as a promising upstream therapeutic target for modulating NF-κB-driven neuroinflammation.

NF-κB signaling is developmentally regulated, with distinct impacts across the lifespan. During adolescence, increased BBB permeability may permit peripheral inflammation to trigger exaggerated central NF-κB activation, potentially contributing to depressive symptoms[94]. In early life, MIA primes offspring microglia, inducing a hypersensitive state that predisposes to ASD via exaggerated NF-κB responses[95]. Furthermore, emerging evidence reveals a reciprocal regulatory relationship between the circadian clock and NF-κB signaling[96]. The core circadian transcription factors BMAL1 and CLOCK can directly repress NF-κB activity by binding to E-box elements in the promoters of NF-κB subunits, thereby controlling their rhythmic expression[97]. Conversely, inflammatory stimuli that activate NF-κB can disrupt circadian gene expression, creating a feedback loop where circadian disruption promotes inflammation, and inflammation impairs clock function[98]. This interaction has clinical relevance for psychiatric disorders.

THERAPEUTIC IMPLICATIONS

Indirect anti-inflammatory strategies

Existing drugs and interventions offer several indirect strategies to modulate NF-κB signaling and counter neuroinflammation. These approaches primarily work by targeting upstream regulatory mechanisms. For instance, antioxidants such as N-acetylcysteine replenish glutathione to quench reactive oxygen species that drive NF-κB activation[99]. Similarly, pharmacologically activating the Nrf2 pathway with compounds, such as sulforaphane or curcumin, enhances cellular antioxidant defenses, thereby suppressing NF-κB activity[100,101]. Another strategy involves modulating immunometabolism; drugs targeting pathways such as mTOR, AMPK, and PPARγ, can reprogram immune cell function and shift glial cells toward an anti-inflammatory state, indirectly inhibiting NF-κB. This principle extends to lifestyle interventions, where physical exercise has been demonstrated to inhibit hippocampal NF-κB via adiponectin and AMPK signaling[102]. In addition, natural multi-target extracts demonstrate efficacy: Ginkgo biloba extract and its flavonoid components reduce pro-inflammatory cytokines and suppress NF-κB activity in models of Alzheimer’s disease, whereas compounds such as α-dimorphecolic acid inhibit microglial NF-κB signaling[103,104]. Notably, several conventional psychiatric medications, including certain antidepressants and mood stabilizers, exhibit off-target immunomodulatory effects, such as reducing peripheral cytokines and inhibiting NF-κB activation in vitro[11,105,106]. Collectively, these strategies highlight the potential of indirectly influencing the NF-κB pathway through redox balance, metabolic modulation, and broad anti-inflammatory actions to alleviate neuroinflammation.

Emerging strategies for directly targeting NF-κB pathways

Natural compounds with multi-target mechanisms represent a promising therapeutic strategy for modulating the NF-κB pathway in neuropsychiatric and neurodegenerative conditions. Resveratrol inhibits IKK/NF-κB activation while also activating the Nrf2 antioxidant pathway, thereby concurrently reducing inflammation and oxidative stress[107]. Similarly, andrographolide covalently modifies the p50 subunit of NF-κB[108]. Recent studies further highlight ALA, which functions through GPR120/β-arrestin2 signaling to inhibit the TAK1/NF-κB/NLRP3 axis in microglia[102]. Beyond natural compounds, other approaches include targeting upstream activators, such as LOX-1 or p38-MAPK, inhibiting kinases such as IKKβ, using proteasome inhibitors to prevent IκBα degradation, and exploring epigenetic modulators such as PCGF1[103].

Toward personalized medicine and biomarkers

Advancing personalized medicine in psychiatric disorders requires the identification of distinct inflammatory biotypes through comprehensive biomarker profiling. A foundational approach is the measurement of oxidative and nitrosative stress markers—including reactive oxygen and nitrogen species, glutathione, and lipid peroxidation products—combined with the assessment of NF-κB pathway activity in peripheral blood mononuclear cells[109,110]. This can be extended to metabolic profiling, where reduced plasma levels of specific fatty acids, such as α-dimorphecolic acid and ALA, correlate with inflammatory status and may serve as auxiliary diagnostic indicators[111]. Clinically, stratification is already feasible using accessible peripheral biomarkers; for instance, combining plasma CRP with leukocyte IL-1β mRNA effectively identifies subgroups with unique NF-κB dysregulation and more severe cognitive deficits in schizophrenia[33]. Furthermore, viral serology—such as cytomegalovirus serostatus—should be considered as a covariate, as it accounts for significant variance in peripheral NF-κB pathway activity[24]. The biomarker landscape is further enriched by dysregulated NF-κB-associated long non-coding RNAs in blood, including CHAST in BD and ANRIL/NKILA in ASD, which show significant diagnostic potential[48,52].

Recent evidence implicates NF-κB as a pivotal molecular node in the pathophysiology of treatment-resistant psychiatric disorders, transcending its traditional role as a mere inflammatory mediator[11]. This positions NF-κB not just as a biomarker of treatment resistance, but as a direct therapeutic target for reversing the inflammatory and neuroplastic deficits that characterize these conditions. Emerging digital medicine paradigms offer novel opportunities to integrate NF-κB biology with real-time patient data. Machine learning models could combine physiological parameters from wearable devices—such as heart rate variability, sleep patterns, and physical activity—with peripheral inflammatory biomarkers, such as NF-κB-associated lncRNAs, to identify inflammatory digital phenotypes[112]. Such interdisciplinary approaches could enable dynamic, personalized treatment strategies. To translate these biomarkers into clinical practice, two operational considerations are essential. First, feasible approaches for measuring NF-κB pathway activity include: Flow cytometry for phospho-p65 in peripheral blood mononuclear cells (PBMCs); quantitative PCR for downstream inflammatory gene signatures; and plasma CRP. Second, interpretation requires adjusting for key confounders, such as metabolic factors, medication exposure and sleep/stress levels.

CONCLUSION

This review highlights the pivotal role of the NF-κB signaling pathway in the pathophysiology of multiple psychiatric disorders, including MDD, schizophrenia, PTSD, BD, and ASD (Figure 1). Research indicates that NF-κB serves as a central molecular node linking peripheral immune dysregulation with central neuroinflammation, thereby influencing key processes, such as synaptic plasticity, glial cell activation, and neuronal function in distinct brain regions. NF-κB exerts cell type-specific effects in microglia, astrocytes, and neurons, often interacting with other signaling pathways including Nrf2, HIF-1α, and NLRP3, thereby shaping neuroinflammatory outcomes. Targeting NF-κB or its regulators holds potential for modulating neuroinflammation. Despite promising preclinical evidence, translating NF-κB-targeted therapies to psychiatric populations faces substantial challenges. First, the BBB limits CNS penetration of many systemically administered inhibitors, necessitating strategies such as nanoparticle delivery or prodrug design. Second, NF-κB’s ubiquitous expression and pleiotropic functions raise safety concerns; systemic inhibition may compromise immune homeostasis, increasing infection risk or impairing tissue repair. Third, achieving cell-type specificity remains difficult, as NF-κB activation in microglia drives pathology, whereas its neuronal activity may support survival and plasticity. Fourth, most direct NF-κB inhibitors remain at preclinical stages, requiring rigorous clinical validation. Future directions should prioritize CNS-penetrant, cell-type-selective approaches and short-course or intermittent dosing strategies to minimize off-target effects while preserving physiological NF-κB functions.

Figure 1 Central role of nuclear factor-κB in psychiatric disorders. Nuclear factor-κB (NF-κB) acts as a key molecular link between peripheral immune dysregulation and central neuroinflammation in conditions including schizophrenia, post-traumatic stress disorder, bipolar disorder, and autism spectrum disorder. Its activation drives cell-type-specific responses in microglia, astrocytes, and neurons, and involves crosstalk with pathways such as nuclear factor erythroid 2-related factor 2 and NOD-, LRR- and pyrin domain-containing protein 3. Therapeutic strategies targeting NF-κB include indirect approaches like exercise and antioxidants, as well as direct inhibitors. Integration of clinical and preclinical evidence supports biomarker-driven personalized medicine. lncRNA: Long non-coding RNA; HIF-1α: Hypoxia-inducible factor 1-alpha; ALA: Α-linolenic acid; LOX-1: Like oxidized low-density lipoprotein receptor-1; NF-κB: Nuclear factor-κB; PTSD: Post-traumatic stress disorder; ASD: Autism spectrum disorder; Nrf2: Nuclear factor erythroid 2-related factor 2; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3.