Dysregulated oxidative stress pathways in schizophrenia : integrating single-cell transcriptomic and human biomarker evidence

Abstract

Background: Schizophrenia is a complex neuropsychiatric disorder whose pathophysiology may involve oxidative stress-induced neuronal damage and inflammation. We conducted a cross-species study to elucidate oxidative stress dysregulation in schizophrenia. Methods: We measured peripheral oxidative stress biomarkers (malondialdehyde [MDA], nitric oxide [NO], reduced glutathione [GSH], superoxide dismutase [SOD], catalase [CAT], advanced protein oxidation products [APOP]), and C-reactive protein (CRP) in antipsychotic-naïve schizophrenia patients and matched controls. We also assayed liver enzymes (ALP, ALT, AST) as indicators of systemic metabolic stress. In parallel, we re-analyzed published single-cell RNA-sequencing data from a Setd1a^+/–^ mouse model of schizophrenia, focusing on prefrontal cortex (PFC) cell types and oxidative stress-related gene expression. Results: Patients with schizophrenia showed markedly elevated MDA and NO (indicators of lipid and nitrosative stress) and significantly reduced antioxidant defenses (GSH, SOD, CAT) versus controls (p < 0.01 for all comparisons). Notably, urban patients exhibited higher oxidative stress biomarker levels than rural patients, implicating environmental contributions. Liver function tests revealed increased ALT, AST, and ALP in schizophrenia, suggesting hepatic/metabolic dysregulation. Single-cell analysis confirmed dysregulated redox pathways in the schizophrenia model; PFC neurons from Setd1a^+/–^ mice displayed significantly lower expression of key antioxidant genes (e.g., Gpx4, Nfe2l2) compared to wild-type, indicating impaired glutathione metabolism. Conclusions: Our integrative data identify convergent oxidative stress imbalances in schizophrenia across species. These findings advance a mechanistic understanding of schizophrenia as a disorder of redox dysregulation and inflammation. They also have translational implications as augmenting antioxidant defenses (for example, with N-acetylcysteine or vitamins C/E) could mitigate oxidative injury and neuroinflammation in schizophrenia, representing a promising adjunct to antipsychotic therapy.