Redox System Dysfunction as a Key Mechanism in Autism Spectrum Disorder Pathogenesis

Autism Spectrum Disorder (ASD) is a complex and multifactorial neurodevelopmental condition whose pathogenesis remains only partially elucidated. Earlier accounts of oxidative stress in ASD often relied on the reductive paradigm of an imbalance between oxidants and antioxidants. In contrast, this narrative review, based on a systematic examination of 1102 publications indexed in scientific databases from 2002 to July 2025, reframes the discussion in terms of redox system dysfunction, a broader and more integrative construct. Here, reactive oxidant species, molecular targets, and reducing/antioxidant counterparts are considered elements of a dynamic circuitry whose maladaptation progressively undermines homeostasis. The sequence of events unfolds in three stages. The first is primary redox dysfunction, manifesting as alterations in metabolic, signaling, and defense pathways. From this disturbance, a second stage arises, marked by functional derailment of cellular compartments-from membranes and cytosol to organelles and nuclei-including mitochondrial and peroxisomal deficits. Ultimately, a third stage emerges, defined by neurodevelopmental alterations such as impaired neurotransmission, synaptic dysfunction, abnormal plasticity, morphogenetic defects, neuroinflammation, and gut-brain-microbiota disarrangements. This progression situates the redox system as a central hub at the interface between human cells and the microbiota, resonating with the ecological and evolutionary principles of the holobiont and the One Health framework. By weaving dispersed evidence into a coherent perspective, this review advances beyond previous analyses, offering a unifying paradigm that connects biochemical dysfunction to clinical heterogeneity in ASD and opens new directions for interdisciplinary research.