The Potential Core Role of the FN1-Hippo Signaling Axis in the Pathological Mechanism of Autism spectrum disorder

Autism Spectrum Disorder (ASD) lacks reliable biomarkers and targeted therapies. This study integrated serum transcriptomics and proteomics from 13 ASD and 13 typically developing (TD) children to elucidate core molecular mechanisms. Differential expression analysis identified 6,563 genes (94.2% upregulated) and 157 proteins (75.2% downregulated), revealing widespread post-transcriptional dysregulation in ASD. Functional enrichment demonstrated abnormalities in energy metabolism, ciliary function, and chemical perception pathways. O2PLS multi-omics integration nominated FN1 as a pivotal cross-omics target, exhibiting transcriptional elevation but proteomic reduction, indicating post-transcriptional perturbation. The Hippo signaling pathway emerged as a key regulatory hub connecting omics layers, with its core components (YAP1, MST1) significantly downregulated. Validation in a valproic acid-induced SH-SY5Y neuronal model confirmed that Hippo pathway inhibition drove FN1 transcriptional upregulation and selectively induced interleukin-6 (IL-6) expression, establishing a novel Hippo-FN1-IL-6 axis. This axis mechanistically links developmental signaling defects and neuroinflammation in ASD pathogenesis. Collectively, we define post-transcriptional dysregulation as a molecular hallmark of ASD and identify the Hippo-FN1-IL-6 cascade as a central pathogenic mechanism. FN1 represents a potential diagnostic biomarker and therapeutic target, providing novel insights for ASD intervention strategies.