The potential core role of the FN1-Hippo signaling axis in the pathological mechanism of autism spectrum disorder
- 1Shandong Provincial Maternal and Child Health Care Hospital affiliated to Qingdao University, Qingdao University
Abstract
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.
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BibTeX
@article{li2026potential,
title = {{The potential core role of the FN1-Hippo signaling axis in the pathological mechanism of autism spectrum disorder}},
author = {Ziyun Li and Mai Gao and Ting Zhang and Lu Yang and Dawei Li and Qian Zhou and Huijuan Liu and Lihong Zhang and Li Zhang and Yan Li},
journal = {Frontiers in Psychiatry},
year = {2026},
month = nov,
doi = {10.3389/fpsyt.2026.1978167},
url = {https://www.frontiersin.org/articles/10.3389/fpsyt.2026.1978167/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The potential core role of the FN1-Hippo signaling axis in the pathological mechanism of autism spectrum disorder
AU - Ziyun Li
AU - Mai Gao
AU - Ting Zhang
AU - Lu Yang
AU - Dawei Li
AU - Qian Zhou
AU - Huijuan Liu
AU - Lihong Zhang
AU - Li Zhang
AU - Yan Li
PY - 2026
DA - 2026/11/09
JO - Frontiers in Psychiatry
DO - 10.3389/fpsyt.2026.1978167
UR - https://www.frontiersin.org/articles/10.3389/fpsyt.2026.1978167/full
AB - 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.
SN - 1664-0640
ER -