Core microRNAs bridging peripheral transcriptomic alterations, brain functional abnormalities, and clinical symptomatology in schizophrenia.

This study adopted a comprehensive multi-omics approach integrating blood microRNA (miRNA) transcriptomic profiles, resting-state functional magnetic resonance imaging (rs-fMRI) neuroimaging data, and clinical symptomatology to elucidate the molecular and biological underpinnings of schizophrenia. miRNA sequencing was performed on peripheral blood samples collected from 43 patients with schizophrenia and 60 age- and sex-matched healthy controls. A total of 65 differentially expressed miRNAs (DEMs) were detected, among which the vast majority (n = 47, |FC| > 1.5, P < 0.05) exhibited significant downregulation, with only 18 showing upregulation. Functional enrichment analyses including Gene Ontology (GO), Disease Ontology (DO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that these DEMs were predominantly enriched in biological processes critical to schizophrenia pathogenesis, such as neuronal development and positive regulation of cellular/biological processes. Partial Least Squares (PLS) correlation analysis further demonstrated robust cross-modal associations among DEMs expression patterns, rs-fMRI-derived brain functional metrics (including amplitude of low-frequency fluctuation, regional homogeneity, and degree centrality), and clinical manifestations evaluated by standardized scales. Furthermore, intersection analysis identified 13 core miRNAs (hsa-miR-144-3p, hsa-let-7g-5p, hsa-miR-15a-5p, hsa-let-7a-5p, miR-144-y, hsa-let-7f-5p, hsa-miR-98-5p, hsa-miR-27b-3p, hsa-miR-126-3p, hsa-miR-16-2-3p, hsa-miR-16-5p, hsa-miR-26b-5p and miR-374-x) that were co-expressed in gene sets linked to both brain function and clinical symptoms, indicating a shared transcriptional regulatory basis underlying the neurobiological and phenotypic features of schizophrenia. Furthermore, our study revealed significant associations between specific miRNAs and depressive symptoms measured by the Hamilton Depression Scale (HAMD), supporting that peripheral miRNA dysregulation is linked not only to core psychotic symptoms but also to common affective sympotoms in schizophrenia. Collectively, the findings of this study provide novel insights into the integrated molecular and functional alterations of schizophrenia, and highlight the unique application value of the multi-omics approach in deciphering the intricate pathogenesis and pathological progression of schizophrenia. These results also lay a critical foundation for the development of miRNA-based diagnostic biomarkers and targeted therapeutic strategies, which hold great significance for guiding future clinical trials and advancing the precision medicine paradigm in schizophrenia research.