The Role of Ferroptosis and Oxidative Stress in Cognitive Deficits Among Chronic Schizophrenia Patients: a Multicenter Investigation

Overview

Journal Schizophrenia (Heidelb)

Date 2025 Jan 11

PMID 39799168

Authors

Zhenlei Peng

Qiyu Jia

Junxiong Mao

Shijie Jiang

Qi Ma

Xiao Luo

Zhiguo An

Anqi Huang

Chuang Ma

Qizhong Yi

Affiliations

Soon will be listed here.

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.

References

Zhang G, Lv S, Zhong X, Li X, Yi Y, Lu Y . Ferroptosis: a new antidepressant pharmacological mechanism. Front Pharmacol. 2024; 14:1339057. PMC: 10800430. DOI: 10.3389/fphar.2023.1339057. View

Sheehan D, Lecrubier Y, Sheehan K, Amorim P, Janavs J, Weiller E . The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1999; 59 Suppl 20:22-33;quiz 34-57. View

Chen K, Lee Y, Yu T, Cheng L, Chao C, Hsieh C . Test-retest reliability and convergent validity of the test of nonverbal intelligence-fourth edition in patients with schizophrenia. BMC Psychiatry. 2021; 21(1):39. PMC: 7805048. DOI: 10.1186/s12888-021-03041-4. View

Peng J, Liu B, Tan W, Hu S, Li B, Zhou J . Association between Body Iron Status and Cognitive Task Performance in a Nationally Representative Sample of Older Adults. Aging Dis. 2024; 16(2):1141-1148. DOI: 10.14336/AD.2019.0064. View

Gil-Berrozpe G, Sanchez-Torres A, de Jalon E, Moreno-Izco L, Fananas L, Peralta V . Utility of the MoCA for cognitive impairment screening in long-term psychosis patients. Schizophr Res. 2019; 216:429-434. DOI: 10.1016/j.schres.2019.10.054. View

Zhang D, Wu X, Xue X, Li W, Zhou P, Lv Z . Ancient dormant virus remnant ERVW-1 drives ferroptosis via degradation of GPX4 and SLC3A2 in schizophrenia. Virol Sin. 2023; 39(1):31-43. PMC: 10877354. DOI: 10.1016/j.virs.2023.09.001. View

Nasreddine Z, Phillips N, Bedirian V, Charbonneau S, Whitehead V, Collin I . The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005; 53(4):695-9. DOI: 10.1111/j.1532-5415.2005.53221.x. View

Skiba R, Chinchani A, Menon M, Lepage M, Lavigne K, Malla A . Overlap between individual differences in cognition and symptoms of schizophrenia. Schizophr Res. 2024; 270:220-228. DOI: 10.1016/j.schres.2024.06.010. View

Lin C, Lin P, Lin C, Lin C, Huang C, Huang Y . Decreased mRNA expression for the two subunits of system xc(-), SLC3A2 and SLC7A11, in WBC in patients with schizophrenia: Evidence in support of the hypo-glutamatergic hypothesis of schizophrenia. J Psychiatr Res. 2015; 72:58-63. DOI: 10.1016/j.jpsychires.2015.10.007. View

10.

Huo L, Lu X, Wu F, Chang C, Ning Y, Zhang X . Elevated activity of superoxide dismutase in male late-life schizophrenia and its correlation with clinical symptoms and cognitive deficits. BMC Psychiatry. 2021; 21(1):606. PMC: 8642951. DOI: 10.1186/s12888-021-03604-5. View

11.

Astudillo A, Balboa M, Balsinde J . Compartmentalized regulation of lipid signaling in oxidative stress and inflammation: Plasmalogens, oxidized lipids and ferroptosis as new paradigms of bioactive lipid research. Prog Lipid Res. 2022; 89:101207. DOI: 10.1016/j.plipres.2022.101207. View

12.

Wu B, Lan T, Hu T, Lee S, Liou J . Validation of a five-factor model of a Chinese Mandarin version of the Positive and Negative Syndrome Scale (CMV-PANSS) in a sample of 813 schizophrenia patients. Schizophr Res. 2015; 169(1-3):489-490. DOI: 10.1016/j.schres.2015.09.011. View

13.

Yang M, Li J, Yang H, Yan L, Liu D, Zhu L . Cognitive Impairment and Psychopathology Are Related to Plasma Oxidative Stress in Long Term Hospitalized Patients With Chronic Schizophrenia. Front Psychiatry. 2022; 13:896694. PMC: 9226302. DOI: 10.3389/fpsyt.2022.896694. View

14.

Li X, Chen J, Feng W, Wang C, Chen M, Li Y . Berberine ameliorates iron levels and ferroptosis in the brain of 3 × Tg-AD mice. Phytomedicine. 2023; 118:154962. DOI: 10.1016/j.phymed.2023.154962. View

15.

Moorthy H, Ramesh M, Padhi D, Baruah P, Govindaraju T . Polycatechols inhibit ferroptosis and modulate tau liquid-liquid phase separation to mitigate Alzheimer's disease. Mater Horiz. 2024; 11(13):3082-3089. DOI: 10.1039/d4mh00023d. View

16.

Feng S, Chen J, Qu C, Yang L, Wu X, Wang S . Identification of Ferroptosis-Related Genes in Schizophrenia Based on Bioinformatic Analysis. Genes (Basel). 2022; 13(11). PMC: 9690569. DOI: 10.3390/genes13112168. View

17.

Hursitoglu O, Orhan F, Belge Kurutas E, Doganer A, Durmus H, Kopar H . Diagnostic Performance of Increased Malondialdehyde Level and Oxidative Stress in Patients with Schizophrenia. Noro Psikiyatr Ars. 2021; 58(3):184-188. PMC: 8419726. DOI: 10.29399/npa.27372. View

18.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

19.

Mahfoud D, Hallit S, Haddad C, Fekih-Romdhane F, Haddad G . The moderating effect of cognitive impairment on the relationship between inner speech and auditory verbal hallucinations among chronic patients with schizophrenia. BMC Psychiatry. 2023; 23(1):431. PMC: 10265809. DOI: 10.1186/s12888-023-04940-4. View

20.

Woods S . Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003; 64(6):663-7. DOI: 10.4088/jcp.v64n0607. View