Network Pharmacology and Molecular Docking Reveal Multi-Target Mechanisms of Luteolin Against Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition influenced by genetic, metabolic, and neuroinflammatory mechanisms. Luteolin, a dietary flavonoid with anti-inflammatory and neuroprotective properties, has recently gained attention as a potential adjunct therapy for ASD. However, its molecular mechanisms remain insufficiently explored. This study employed a network pharmacology framework to identify putative molecular targets of luteolin in ASD. Targets were predicted using SwissTargetPrediction and intersected with ASD-related genes retrieved from GeneCards (relevance score >1). Protein–protein interaction (PPI) networks were constructed using STRING and analyzed via Cytoscape and CytoHubba to determine key hub genes. Functional enrichment was performed using GO and KEGG analyses. Representative hub proteins including CA4, MET, DRD4, AKT1, and IGF1R from major ASD-related pathways were further validated through CB-Dock molecular docking. A total of 39 overlapping targets were identified. Hub nodes (AKT1, SRC, ESR1, GSK3B, PTGS2, MMP9, PARP1, IGF1R, AR, ESR2) were strongly enriched in pathways central to ASD pathology, including nitrogen metabolism, dopaminergic synapse, HIF-1 signaling, adherens junction, and PI3K–Akt signaling. Molecular docking confirmed strong ligand–protein interactions, with binding energies ranging from −7.7 to −9.8 kcal/mol, indicating favorable affinity particularly with AKT1 (−9.8 kcal/mol), DRD4 (−8.9 kcal/mol), and IGF1R (−8.3 kcal/mol). This integrative analysis suggests that luteolin exerts multitarget effects relevant to ASD through modulation of synaptic signaling, oxidative stress, inflammatory pathways, and excitatory/inhibitory neurotransmission. These findings provide mechanistic support for luteolin as a potential complementary therapeutic agent for ASD and justify further in clinical investigations.