Validation and Functional Exploration of Exosome-Derived ITGA9-AS1 and WNT5A-AS1 as Candidate Diagnostic Biomarkers for Schizophrenia

<h4>Objective</h4>Schizophrenia lacks objective biomarkers, and its complex aetiology demands epigenetic insight. Given the regulatory roles of long non-coding RNAs (lncRNAs) in the nervous system and brain-relevant signals in peripheral exosomes, we evaluated lncRNA expression in patient blood cells and plasma exosomes, assessed their diagnostic value, and explored potential functions and mechanisms.<h4>Methods</h4>Differentially expressed lncRNAs in schizophrenia-related exosomes were identified from GEO (GSE228881), and 15 candidates were selected for validation. In a clinical cohort, RT-qPCR assessed their expression in peripheral blood cells and plasma exosomes. Diagnostic accuracy was evaluated by ROC analysis. Top dysregulated lncRNAs underwent bioinformatic analyses: subcellular localization, evolutionary conservation, ceRNA network construction, and GO/KEGG enrichment.<h4>Results</h4>ITGA9-AS1 and WNT5A-AS1 were significantly upregulated in both peripheral blood cells and plasma exosomes from patients. Both showed favorable diagnostic potential, with AUC values of 0.8422 and 0.8073, respectively, in peripheral blood; their combination yielded an AUC of 0.9180. Bioinformatics analysis revealed that ITGA9-AS1 primarily localizes to the cytoplasm, whereas WNT5A-AS1 is enriched in exosomes, with both exhibiting high evolutionary conservation. Functional predictions suggest ITGA9-AS1 may regulate neuroplasticity-related pathways such as "long-term potentiation" and "cAMP signaling pathway" via a ceRNA mechanism. WNT5A-AS1 may mediate intercellular communication through exosomes, influencing developmental and metabolic pathways, including the "Notch signaling pathway" and "cysteine and methionine metabolism".<h4>Conclusion</h4>Our findings suggest that ITGA9-AS1 and WNT5A-AS1 are highly promising biomarker candidates for schizophrenia. They may be involved in the disease process through distinct mechanisms (intracellular regulation and intercellular communication), thus providing a new theoretical framework and suggesting potential therapeutic targets.