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

Researchers reviewed over 1,000 studies to understand how cell damage from unstable molecules might contribute to autism. They propose that autism develops in three stages: first, problems with how cells process energy and communicate; second, damage to cell parts like mitochondria; and third, brain development issues affecting communication, learning, and gut health. This new way of thinking connects cell-level problems to the diverse symptoms seen in autism.

This narrative review examined 1,102 publications to propose a new framework for understanding autism spectrum disorder (ASD) through redox system dysfunction. Rather than viewing oxidative stress as a simple imbalance, the authors describe a three-stage progressive model: primary redox dysfunction affecting metabolic and signaling pathways, followed by cellular compartment disruption including mitochondrial deficits, culminating in neurodevelopmental alterations including impaired neurotransmission, synaptic dysfunction, neuroinflammation, and gut-brain-microbiota disruptions. This framework positions the redox system as a central hub connecting biochemical dysfunction to clinical diversity in ASD, integrating concepts from holobiont and One Health perspectives to provide a unifying paradigm for future interdisciplinary research.

The redox dysfunction framework may guide development of targeted interventions addressing metabolic, mitochondrial, and inflammatory pathways in ASD. Could inform personalized treatment approaches based on redox system status and support integrated care addressing gut-brain-microbiota interactions.

As a narrative review, findings represent theoretical synthesis rather than empirical evidence. The three-stage model requires validation through prospective studies. No information provided about study quality assessment or potential publication bias in the reviewed literature.

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.