Upregulation of circSUCO22-20 in schizophrenia: clinical correlation with systemic inflammation and in vitro pro-apoptotic mechanisms.

BACKGROUND: Emerging evidence links dysregulation of circular RNAs (circRNAs) to neuropsychiatric disorders, but their pathophysiological roles in schizophrenia (SCZ) remain unclear. We investigated the clinical significance, biological function, and underlying mechanisms of circSUCO22-20 in SCZ. METHODS: Previous whole-transcriptome sequencing identified circSUCO22-20 as differentially expressed in SCZ. Sanger sequencing and RNase R digestion confirmed its covalently closed-loop structure. RT-qPCR validation was performed in 158 patients with SCZ and 158 healthy controls. Associations with Positive and Negative Syndrome Scale (PANSS) scores and systemic inflammatory indicators were assessed using Pearson correlation and restricted cubic spline (RCS) analyses. Cell Counting Kit-8 (CCK-8) and apoptosis assays were used to detect the viability and apoptosis of MK-801 (dizocilpine)-treated SH-SY5Y cells. A dual-luciferase assay was used to confirm the binding relationships among circSUCO22-20, hsa-miR-3913-3p, and SLC7A11. The GSE25673 dataset (iPSC-derived neurons) was analyzed for downstream validation. RESULTS: circSUCO22-20 was significantly upregulated in both patients with SCZ and MK-801-treated SH-SY5Y cells. RCS analysis revealed significant non-linear dose-response correlations between circSUCO22-20 and white blood cell (WBC) count (Poverall = 0.035, Pnon-linear = 0.011), neutrophil count (NEUT) (Poverall = 0.018, Pnon-linear = 0.005), and lymphocyte percentage (LYMPH%) (Poverall = 0.031, Pnon-linear = 0.029). Knockdown restored cell viability and attenuated apoptosis, whereas overexpression exacerbated neuronal injury. Mechanistically, circSUCO22-20 acted as a ceRNA by sponging hsa-miR-3913-3p, thereby modulating SLC7A11 expression. Bioinformatic analysis confirmed SLC7A11 upregulation in SCZ iPSC-derived neurons. CONCLUSION: circSUCO22-20 is upregulated in SCZ and correlates with systemic inflammation. By modulating the hsa-miR-3913-3p/SLC7A11 axis, it exacerbates neuronal apoptosis, supporting its potential as a diagnostic biomarker and therapeutic target for SCZ.