The role of ferroptosis and oxidative stress in cognitive deficits among chronic schizophrenia patients: a multicenter investigation

Abstract

Oxidative stress (OS) is crucial in schizophrenia (SCZ) pathology. Ferroptosis, a recently discovered cell death pathway linked to OS, might contribute to the development of SCZ. This study investigated the association between ferroptosis markers and cognitive impairments in chronic SCZ patients. A retrospective analysis was conducted on 204 chronic SCZ patients with cognitive deficits and 216 healthy controls (HC) matched for relevant characteristics. Plasma levels of ferroptosis and OS markers, including iron, ferritin (FE), transferrin (TF), glutathione peroxidase 4 (GPX4), long-chain acyl-CoA synthetase 4 (ACSL4), glutathione (GSH), sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured. Standardized assessments like the positive and negative syndrome scale (PANSS), and Montreal Cognitive Assessment (MoCA) were used to evaluate psychiatric symptoms, and cognitive function. SCZ patients showed significant differences in markers compared to the HC group (P < 0.01). Multiple linear regression analysis revealed that decreased GSH and iron levels, along with elevated SOD levels, were significantly associated with the overall severity of psychiatric symptoms. Additionally, reduced GPX4 levels and increased ACSL4 and FE levels were significantly linked to negative symptoms and cognitive impairments. Notably, GPX4 emerged as a key predictor for cognitive function in abstraction and language domains. Our study revealed alterations in the altered plasma levels of GPX4, GSH, iron, ACSL4, FE, and SOD in chronic SCZ patients, which might indicate a close association between biomarkers of ferroptosis and OS and the psychiatric symptoms and cognitive deficits observed in these individuals.

Fig. 1. Concentration of ferroptosis and OS-related biomarkers in SCZ and HC groups.

Panels (a) through (j) depict the concentration levels of the following biomarkers in both groups: a glutathione peroxidase 4 (GPX4), b glutathione (GSH), c iron, d transferrin (TF), e sirtuin 1 (SIRT1), f nuclear factor erythroid 2-related factor 2 (Nrf2), g acyl-CoA synthetase long-chain family member 4 (ACSL4), h ferritin (FE), i superoxide dismutase (SOD), and j malondialdehyde (MDA). ^**P < 0.01; ^***P < 0.001.

Fig. 2. Correlation between various ferroptosis and OS markers with the positive and negative syndrome scale (PANSS) scores in the SCZ group.

a Acyl-CoA synthetase long-chain family member 4 (ACSL4) levels vs PANSS scores, b ferritin (FE) levels vs PANSS scores, c superoxide dismutase (SOD) levels vs PANSS scores, d malondialdehyde (MDA) levels vs PANSS scores, e glutathione peroxidase 4 (GPX4) levels vs PANSS scores, f glutathione (GSH) levels vs PANSS scores, g transferrin (TF) levels vs PANSS scores, and h iron levels vs PANSS scores. ^*P < 0.05; ^**P < 0.01; ^***P < 0.001.

Fig. 3. Correlation between various ferroptosis and OS markers with the negative symptoms (N) sub-scores in the SCZ group.

a Acyl-CoA synthetase long-chain family member 4 (ACSL4) levels vs N sub scores, b ferritin (FE) levels vs N sub scores, c malondialdehyde (MDA) levels vs N sub scores, d glutathione peroxidase 4 (GPX4) levels vs N sub scores, e glutathione (GSH) levels vs N sub scores, f transferrin (TF) levels vs N sub scores, and g sirtuin 1 (SIRT1) levels vs N sub scores. ^*P < 0.05; ^**P < 0.01; ^***P < 0.001.

Fig. 4. Correlation between various ferroptosis and OS markers with the general psychopathology symptoms (G) sub-scores in the SCZ group.

a Acyl-CoA synthetase long-chain family member 4 (ACSL4) levels vs G sub scores, b ferritin (FE) levels vs G sub scores, c superoxide dismutase (SOD) levels vs G sub scores, d glutathione (GSH) levels vs G sub scores, e transferrin (TF) levels vs G sub scores, and f iron levels vs G sub scores. ^*P < 0.05; ^**P < 0.01; ^***P < 0.001.

Fig. 5. Correlation between various ferroptosis and OS markers with the Montreal cognitive assessment (MoCA) scores in the SCZ group.

a Glutathione peroxidase 4 (GPX4) levels vs MoCA scores, b glutathione (GSH) levels vs MoCA scores, c transferrin (TF) levels vs MoCA scores, d sirtuin 1 (SIRT1) levels vs MoCA scores, e acyl-CoA synthetase long-chain family member 4 (ACSL4) levels vs MoCA scores, f ferritin (FE) levels vs MoCA scores, g superoxide dismutase (SOD) levels vs MoCA scores, and h malondialdehyde (MDA) levels vs MoCA scores. ^**P < 0.01; ^***P < 0.001.