Metabolic Dysregulation and Metabolite-Targeted Interventions in Autism Spectrum Disorder: Mechanisms and...

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder marked by impaired social communication and restricted repetitive behaviors. Metabolic dysregulation is increasingly recognized as a key intermediate mechanism linking genetic and environmental factors to abnormal neurodevelopment in ASD. This review summarizes ASD-related metabolic abnormalities involving gut microbial metabolites, energy metabolism, neurotransmitter pathways, and immune-metabolic crosstalk. Such metabolic disturbances affect neurodevelopment via immune activation, oxidative stress, mitochondrial dysfunction, and disrupted neurotransmitter homeostasis, ultimately impairing synaptic plasticity and neural connectivity. We also outline the preclinical and clinical progress of metabolite-targeted interventions, which show potential to modulate relevant metabolic pathways. However, it should be noted that improvements in specific metabolic biomarkers may only be associated with, rather than definitively drive, behavioral changes. However, current studies are constrained by inconsistent trial designs, small cohorts, and inadequate mechanistic verification; furthermore, interindividual metabolic heterogeneity limits universal intervention efficacy. We discuss clinical translation barriers and propose future priorities: defining metabolic subtypes, validating biomarkers, and developing precision metabolic interventions. Elucidating these metabolic mechanisms will advance targeted, personalized therapies to improve neurodevelopmental outcomes in ASD.