The potential core role of the FN1-Hippo signaling axis in the pathological mechanism of autism spectrum disorder

Background Autism Spectrum Disorder (ASD) remains poorly understood in molecular pathogenesis, and lacks reliable peripheral biomarkers and targeted interventions. Objective This study aimed to identify cross-omics molecular signatures and core regulatory pathways in ASD by integrating serum transcriptomic and proteomic data from children with ASD and typically developing (TD) children. Methods Serum transcriptomics and label-free data-independent acquisition (label-free DIA) quantitative proteomics were analyzed in 13 children with ASD and 13 age- and sex-matched TD controls. Differential expression analysis, functional enrichment, and two-way orthogonal partial least squares (O2PLS) multi-omics integration were performed. A valproic acid (VPA)-induced SH-SY5Y neuronal differentiation model was used to preliminarily validate the expression patterns of the Hippo signaling pathway and its downstream molecular events. Results We identified 6,563 differentially expressed genes (DEGs, 94.2% upregulated) and 157 differentially expressed proteins (DEPs, 75.2% downregulated), which demonstrated widespread post-transcriptional dysregulation in ASD serum. Functional enrichment analyses highlighted aberrations in energy metabolism, ciliary function, and chemical perception. O2PLS integration nominated Fibronectin-1 (FN1) as a pivotal cross-omics target, with elevated transcription but reduced protein abundance. The Hippo signaling pathway emerged as a central regulatory hub, with core its components significantly downregulated at the mRNA level. In vitro experiments revealed that VPA-triggered neuronal dysregulation was accompanied by Hippo pathway gene suppression, FN1 transcriptional upregulation, and selective induction of interleukin-6 (IL-6), suggesting a putative Hippo-FN1-IL-6 regulatory axis. Conclusion Post-transcriptional dysregulation represents a prominent molecular feature of ASD serum. The proposed Hippo-FN1-IL-6 cascade may provide a mechanistic link between developmental signaling defects and neuroinflammation in ASD pathogenesis. FN1 holds potential as a candidate diagnostic biomarker and therapeutic target, yet its clinical utility and the underlying detailed regulatory mechanisms require further validation in independent large-scale cohorts.