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

Scientists studied a protein called CDKN1A in autism using rat models. When they reduced this protein in rats with autism-like behaviors, the animals showed improvements in social skills, less anxiety, and better learning. The protein seems to cause brain inflammation through a pathway called IL-17. This research suggests that targeting this protein might help develop new autism treatments, though much more research is needed before any human applications.

This study investigated the role of CDKN1A (a cell cycle regulatory protein) in autism spectrum disorder using bioinformatics analysis and rat models. Researchers created an ASD model using maternal LPS injection and found that CDKN1A was elevated in autism-related conditions. When CDKN1A was suppressed, ASD-like behaviors improved, including better social interaction, reduced anxiety, and enhanced learning and memory. The study identified that CDKN1A works through the IL-17 inflammatory pathway to promote neuroinflammation and oxidative stress.

In laboratory cell studies, reducing CDKN1A decreased inflammation and cell death in microglial brain cells. The researchers propose CDKN1A as a potential therapeutic target for autism treatment.

While promising for identifying novel therapeutic targets, this preclinical research requires extensive human validation before clinical application. The IL-17 pathway represents a potential intervention point, but safety and efficacy in humans remain unknown. Current findings are too preliminary to influence clinical practice.

Single animal model study using LPS-induced autism model which may not fully represent human autism complexity. No sample sizes reported. Lack of human validation data. Short-term effects only examined. Unknown whether findings translate across different autism subtypes or severities.

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.