Aug 2026· Frontiers in Immunology· Vol 17· 0 citations· 66 references
Medicine
TL;DR
Early-life oxidative stress is an upstream pathogenic event associated with persistent NFκB activation and neuroinflammation in ASD, and early redox modulation as a potential therapeutic strategy is highlighted.
Abstract
Background Oxidative stress and immune dysregulation are hallmark features of autism spectrum disorder (ASD), yet whether oxidative imbalance acts as an upstream trigger of immune activation remains unclear. The redox-sensitive transcription factor NFκB represents a potential mechanistic link. We investigated whether early-life oxidative stress contributes to persistent NFκB activation and neuroinflammation in ASD. Methods Umbilical cord blood and peripheral blood from ASD and typically developing children were analyzed for redox markers (GSH/GSSG ratio, malondialdehyde, 8-oxo-dG), NFκB activation (p65 DNA-binding and nuclear translocation), and inflammatory gene expression. The mechanistic relationship between oxidative stress and NFκB signaling was investigated in prenatal valproic acid (VPA)-exposed mice using antioxidant intervention (N-acetylcysteine, NAC), NFκB inhibition (Bay 11-7082), pro-oxidant challenge, behavioral assays, and primary amygdala neuron models. Results ASD children exhibited persistent oxidative imbalance detectable at birth, accompanied by increased NFκB activation and pro-inflammatory gene expression. VPA-exposed mice recapitulated these molecular and behavioral abnormalities. In primary neurons, oxidative stress directly enhanced NFκB activity and promoter binding, whereas antioxidant and mitochondrial-targeted approaches suppressed NFκB activation. Developmentally, oxidative stress preceded sustained NFκB activation, and prenatal, but not postnatal, NAC treatment prevented these abnormalities. NAC restored redox homeostasis, reduced NFκB signaling, and improved behavioral deficits, whereas NFκB inhibition alone attenuated inflammatory responses but failed to correct oxidative imbalance or behavioral abnormalities. Conclusion Early-life oxidative stress is an upstream pathogenic event associated with persistent NFκB activation and neuroinflammation in ASD. NFκB primarily mediates inflammatory signaling, while oxidative stress likely contributes to ASD-related behaviors through additional downstream pathways. These findings highlight early redox modulation as a potential therapeutic strategy.
Oxidative stress (OS) represents a pathological imbalance between pro-oxidant production
and antioxidant defense systems, resulting in the excessive accumulation of reactive oxygen species
(ROS) and subsequent molecular damage. Although low physiological levels of ROS are essential
for cellular signaling, synaptic plasticity, and immune responses, sustained ROS overproduction
disrupts redox homeostasis. It induces oxidative damage to lipids, proteins, and nucleic acids. The
brain is particularly vulnerable to oxidative injury because of its high oxygen consumption, abundant
lipid content, and comparatively limited antioxidant capacity. Mounting evidence implicates oxidative
stress as a central contributor to the pathogenesis of major neurodegenerative disorders, including
Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s
disease (HD), and epilepsy. Shared mechanisms include mitochondrial dysfunction, impaired
antioxidant defenses, excitotoxicity, neuroinflammation, and protein aggregation, while disease-
specific pathways involve dopamine quinone toxicity in PD, mutant SOD1-associated redox
imbalance in ALS, amyloid-β-mediated metal catalysis in AD, and mutant huntingtin-induced mitochondrial
injury in HD. Biomarkers such as F2-isoprostanes, malondialdehyde, protein carbonyls, 3-
nitrotyrosine, and 8-hydroxy-2′-deoxyguanosine provide measurable indices of oxidative damage,
though their clinical translation remains limited. This review critically evaluates the mechanistic
evidence linking oxidative stress to neurodegeneration, distinguishes oxidative stress from oxidative
damage, and discusses the translational challenges associated with antioxidant-based therapeutic
strategies.
Priyanka Yadav, Dinesh Kumar, Anil Kumar et al.· Current Neuroscience· 0 citations
BACKGROUND
Chronic inflammatory disorders represent a major global health burden characterized by persistent immune activation, oxidative stress, and progressive tissue dysfunction. Dysregulated redox signaling has positioned the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (Nrf2) axis as an emerging therapeutic target.
METHODS
This review critically examines the mechanistic architecture and context-dependent regulation of KEAP1-Nrf2 signaling across chronic inflammatory disorders, integrating disease-specific evidence, signaling crosstalk, quantitative preclinical findings, therapeutic modulators, nanoenabled delivery systems, clinical evidence, patent trends, and artificial intelligence-assisted drug discovery strategies.
RESULTS
KEAP1-Nrf2 signaling extends beyond antioxidant defense to regulate immunometabolic homeostasis, mitochondrial function, inflammatory signaling, and cellular stress adaptation. Crosstalk with NF-κB, MAPK, PI3K/Akt, and inflammasome-associated pathways contributes to disease-specific inflammatory responses. Preclinical evidence supports natural and synthetic Nrf2 modulators, while nanotechnology-based approaches may improve delivery and tissue specificity. However, dose optimization, bioavailability, off-target effects, long-term safety, and patient heterogeneity remain important translational challenges.
CONCLUSION
KEAP1-Nrf2 represents a context-dependent therapeutic axis with substantial potential across chronic inflammatory diseases. Integrating quantitative evidence, precision delivery, biomarker-guided approaches, and computational strategies may facilitate clinical translation while addressing risks associated with sustained pathway activation.
Abdul Shadab· Immunological Investigations· 0 citations
Multi-dimensional early warning markers based on inflammatory factors, mitophagy-related molecules, epigenetic markers and nutritional exposure indicators, as well as potential intervention strategies such as nutritional supplementation, anti-inflammatory and pro-mitophagy targeting the above pathways were summarized, in order to provide a theoretical reference for the primary prevention of PD.
Qi Li, Zhixiang Jia, Musi Ji et al.· Frontiers in Nutrition· 0 citations
Early-life oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) and reactive nitrogen species (RNS) and antioxidant defenses, has increasingly been proposed as an important contributor to the developmental origins of childhood asthma. Prenatal and early postnatal exposures—including pollutants, tobacco smoke, maternal distress, nutritional imbalance, and allergen-derived oxidase activity—may disrupt epithelial integrity and redox-regulated immune pathways, potentially predisposing the developing lung to allergic inflammation. To synthesize current mechanistic and epidemiologic evidence on how oxidative stress during early life may contribute to asthma development, with particular focus on environmental drivers, redox–immune interactions, and gene-environment susceptibility. A structured review of PubMed, Scopus, and Embase identified peer-reviewed English-language studies from birth cohorts, mechanistic models, and biomarker analyses evaluating oxidative stress, antioxidant capacity, and asthma-related outcomes. Environmental oxidants and nutritional deficiencies may increase ROS production, promoting epithelial injury, activation of redox-sensitive pathways such as NF-κB and MAPK, and the release of epithelial alarmins including IL-33, IL-25, and thymic stromal lymphopoietin (TSLP). These signals can influence innate immune activation and antigen-presenting cell function, favoring Th2/Th17-biased immune responses. Genetic variants in antioxidant pathways, including GSTM1, GSTP1, and Nrf2, may further modify susceptibility to oxidant exposures. Epidemiologic studies from birth cohorts report associations between early-life oxidative exposures, reduced lung growth, wheezing, allergic sensitization, and asthma risk. Current mechanistic and epidemiologic evidence suggests that oxidative stress may represent an important biological pathway linking early-life environmental exposures with asthma susceptibility, although further studies are needed to clarify its role within the complex network of factors contributing to asthma development.
Michele Piazza, M. Zaffanello, A. Zicari et al.· Exploration of Medicine· 0 citations
TAF15 is a DNA/RNA-binding protein involved in RNA processing whose dysfunction has been implicated in neurodegenerative diseases, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, the relationship between TAF15 expression levels and neurodegeneration, as well as the specific downstream pathways mediating its neurotoxicity, remain unclear. Here, we find a consistent upregulation of TAF15 in prefrontal cortex neurons from patients across multiple FTD and ALS subtypes. Both in vitro and in vivo experiments demonstrate that neuronal TAF15 overexpression triggers oxidative stress, leading to neurotoxicity and gliosis. Mice overexpressing TAF15 in medial prefrontal cortex (mPFC) neurons exhibit heightened anxiety and impaired cued fear-conditioning responses. Notably, these pathological and behavioral phenotypes are rescued by the antioxidant N-acetylcysteine amide (NACA), supporting a role for oxidative stress in TAF15-associated neurodegeneration. Together, this study elucidates a TAF15-oxidative stress axis in neurodegeneration, providing a conceptual framework for future therapeutic development.
Tuo Yi, Haoyuan Guan, Jun Li et al.· Cell Reports· 0 citations
A stage-dependent mitochondrial dysfunction–redox imbalance–NLRP3 inflammasome axis provides a testable stage-dependent framework for interpreting chronic, self-amplifying neuroinflammation in AD and may inform biomarker-guided, combinatorial therapeutic strategies.
Si-Yu Li, Jun-Tao Jin, Ying-Ying Liu et al.· Journal of Alzheimer's Disea...· 1 citation
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