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Validation and Functional Exploration of Exosome-Derived ITGA9-AS1 and WNT5A-AS1 as Candidate Diagnostic Biomarkers
Yangyang Xu1,2, Yan Wang3, Fuyi Qin4
1Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China.
Objective:
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.
Methods:
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.
Results:
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".
Conclusion:
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.
