Oxidative stress response and NRF2 signaling pathway in autism spectrum disorder

Abstract

The prevalence of autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by impairments in social communication and restricted/repetitive behavioral patterns, has increased significantly over the past few decades. The etiology of ASD involves a highly complex interplay of genetic, neurobiological, and environmental factors, contributing to significant heterogeneity in its clinical phenotype. In the evolving landscape of ASD research, increasing evidence suggests that oxidative stress, resulting from both intrinsic and extrinsic factors, may be a crucial pathophysiological driver in ASD, influencing neurodevelopmental processes that underlie behavioral abnormalities. Elevated levels of oxidative stress biomarkers, including lipid peroxides, protein oxidation products, and DNA damage markers, alongside deficient antioxidant enzyme activity, have been consistently linked to ASD. This may be attributed to dysregulated activity of nuclear factor erythroid 2-related factor 2 (NRF2), a pivotal transcription factor that maintains cellular redox homeostasis by orchestrating the expression of genes involved in antioxidant defenses. Here, we summarize the converging evidence that redox imbalance in ASD may result from NRF2 dysregulation, leading to reduced expression of its target genes. We also highlight the most promising antioxidant compounds under investigation, which may restore NRF2 activity and ameliorate ASD behavioral symptoms.

Keywords: Antioxidants; Autism; Inflammation; NRF2; Oxidative stress.

Fig. 1

Oxidative stress in the context of autism spectrum disorder. The figure depicts a shift from physiological ROS levels, essential for normal redox signaling, to excessive concentrations that promote cellular damage. Endogenous sources of ROS include mitochondrial oxidative phosphorylation, NADPH oxidases, oxidative enzymes, peroxisomal activity, and endoplasmic reticulum stress, alongside environmental factors, such as xenobiotic exposure. Increased levels of ROS, such as hydrogen peroxide (H₂O₂), superoxide (O₂•^-), and hydroxyl radicals (•OH), can cause oxidative damage to lipids, proteins, and DNA, affecting cellular homeostasis and neurodevelopment. These redox alterations are also associated with inflammatory activity at both systemic and brain levels. Overall, these processes impair neuronal and synaptic function, cause changes in dendritic spine density, and affect synaptic pruning. Together, these converging events contribute to the pathophysiology of autism spectrum disorder.

Fig. 2

Canonical and non-canonical regulation of NRF2 stability and activity. Under homeostatic conditions, NRF2 is constitutively ubiquitinated by the KEAP1–CUL3–RBX1 E3 ligase complex and degraded via the proteasome. Oxidative or electrophilic stress modifies reactive cysteines on KEAP1, impairing NRF2 ubiquitination and allowing its nuclear translocation. Instead of KEAP1, NRF2 can also be regulated through GSK-3β–mediated phosphorylation, which targets NRF2 for β-TrCP–dependent ubiquitination via the CUL1–RBX1 complex. Likewise, phosphorylation by kinases such as AMPK, CK2, and PKC enhances NRF2 stability and promotes its nuclear accumulation. In the nucleus, NRF2 heterodimerizes with small Maf proteins and binds to AREs, inducing transcription of cytoprotective genes including HO-1, NQO1, SOD, CAT, and enzymes involved in glutathione synthesis and the pentose phosphate pathway (e.g., GCLC, GCLM, G6PD, 6PGD, ME1, IDH1). These pathways collectively orchestrate adaptive responses to maintain cellular redox homeostasis.