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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317721 | GEO | 2026/02/01

REPOSITORIES: GEO

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Project description:Objective: Adult Still’s disease (ASD) is a systemic disorder of unknown etiology characterized by high spiking fever, rash and arthritis. The purpose of this study was to determine the pathogenic roles of specific genes in ASD. Methods: Differentially expressed genes (DEGs) were examined by DNA microarray and validated by quantitative PCR using monocytes isolated from patients with active-ASD, inactive-ASD and healthy controls. The correlation between validated DEGs and ASD activity was analyzed. After inflammasome activation with LPS and Nigericin, the production of IL-1β, IL-18, inflammasome and autophagy related proteins in DEGs-overexpressing THP-1 cells was carried out by ELISA or western blotting. DEGs-overexpressing THP-1 cells were treated with an inhibitor of autophagy followed by assessment of IL-1β and IL-18 production by ELISA and western blotting method.Conclusions: The overexpression of PLAC8 in monocytes might play a regulatory role in the production of IL-1β and IL-18 by the enhancement of autophagy, resulting in the suppression of ASD. Results:A total of 68 genes were highly expressed in monocytes isolated from active-ASD patients, relative to their expression in inactive-ASD patients and healthy controls. After validation of expression of 13 genes (CLU, FCGR1B, PLAC8, TLR1, S100A12, CD55, PIM1, BCL2A1, SOD2, PLSCR1, CYP1B1, STEAP4, IL1RN), the expression of PLAC8 was significantly higher in active-ASD patients than the other groups. In ASD, PLAC8 expression level correlated with serum levels of CRP, ferritin and IL-18. Stimulation of monocytes with lipopolysaccharide resulted in PLAC8 upregulation. LPS or Nigericin stimulation of PLAC8-overexpressing THP-1, but not THP-1 cells< was associated with significant decrease in IL-1β and IL-18 production. PLAC8 overexpressing in THP-1 cells was associated with enhanced autophagy and suppression of IL-1β and IL-18 production. Conclusions: PLAC8 upregulation in monocytes seemed to play a regulatory role in the production of IL-1β and IL-18 through enhanced autophagy, resulting in suppression of ASD. The results highlight the role of PLAC8 in the pathogenesis of ASD and suggest its potential suitability as a therapeutic target in ASD.

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

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