Oxidative stress response and NRF2 signaling pathway in autism spectrum disorder

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.