Knockdown of CDKN1A Suppresses the IL-17 Pathway to Inhibit Oxidative Stress and Alleviate Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social interaction, communication deficits, and repetitive behaviors. However, the underlying molecular mechanisms remain elusive. This study aims to investigate the role of cyclin-dependent kinase inhibitor 1 A (CDKN1A) in ASD. This study integrated multi-omics bioinformatics analysis to identify differentially expressed genes (DEGs) related to oxidative stress in ASD. Hub genes were screened using machine learning models. In vivo, an ASD rat model was established by maternal lipopolysaccharide (LPS) injection. Behavioral tests (open field, three-chamber social, morris water maze) were performed. Histopathology change was observed by hematoxylin-eosin staining. In vitro, LPS-stimulated BV2 microglia were treated with IL-17A for feedback experiments. Enzyme-linked immunosorbent assay was carried out to measure inflammatory factors and oxidative stress indicators. Western blot was used to detect protein expression. Bioinformatics analysis revealed 30 DEGs, with CDKN1A emerging as a prominent hub gene associated with oxidative stress. ASD model rats exhibited behavioral deficits, neuroinflammation, and hippocampal neurodegeneration. CDKN1A knockdown significantly attenuated these phenotypes, improving social interaction, reducing anxiety-like behaviors, and enhancing spatial learning and memory. Moreover, IL-17 pathway was screened as downstream pathway of CDKN1A. CDKN1A silencing suppressed LPS-induced apoptosis, inflammation, and oxidative stress in BV2 microglial cells, which was weakened by IL-17A. CDKN1A drives ASD pathogenesis via IL-17 pathway activation. Its suppression mitigates neuroinflammation, oxidative stress, and behavioral impairments, establishing CDKN1A as a novel therapeutic target for ASD. Trial Registration: Clinical trial number: Not applicable.