Schizophrenia is a chronic psychological disorder identified by hallucinations, delusions, and confusion, as well as motivational and cognitive dysfunction (Kahn et al., 2015). Schizophrenic patients face a fatality risk about two to three times greater than the standardized rate of mortality, and this difference increases every year (McGrath et al., 2008). Suicide was considered one of the major death causes in patients with schizophrenia over the past five-years World Health Organization study of psychiatric patients (White et al., 2009), and attempted suicide rates in patients with schizophrenia were 10–20 times higher (Balhara and Verma, 2012). A large number of studies have demonstrated that environmental factors play an influential role in the pathogenesis of schizophrenia. The findings of these studies suggest that the disorder may be caused by multiple factors, including intrauterine infections, micronutrient deficiencies, and fetal hypoxia. As a result, these factors can interact in complex ways with the macro-structural environment, including psychological, social, cultural, and economic contexts, in order to increase the risk of schizophrenia (Brown, 2011).

Accidental cell death (ACD) and programmed cell death (PCD) are the two divisions of cell death. PCD is characterized by distinct morphological features and competency-dependent biochemical mechanisms and is considered an important component of a variety of processes (Elmore, 2007). Twelve types have now been identified in studies of PCD, including Apoptosis, Pyroptosis, Ferroptosis, Autophagy, Necroptosis, and Cuproptosis Parthanatos Entotic cell death, Netotic cell death, Lysosome-dependent cell death, Alkaliptosis and Oxiptosis (Zou et al., 2022). The introduction to Gasdermin family (Yu et al., 2021) and the connection of innate immunity and disease with pyroptosis have increased the scope of its research. The accumulation of reactive lipid-based oxygen species resulting in a regulatory form of cell death through an iron-dependent process was termed as the iron death in 2012 (Hirschhorn and Stockwell, 2019). Similarly, the accumulation of Cu in mitochondria causing the aggregation of lipidated TCA cycle enzymes via direct Cu binding led to copper death which is the most recent form of cell death (Cobine and Brady, 2022).

PCD causes abnormal neuronal numbers and pathological neurodevelopment not only in typical neurodegenerative diseases such as Alzheimer’s disease but also in many neurodevelopmental disorders such as schizophrenia and autism (Margolis et al., 1994). However, there have been few detailed functional studies on PCD in schizophrenia, therefore this research dealt with the development of a predictive model with good diagnostic efficacy using PCD-related genes, as well as hypotheses about the possibility of other pharmacological treatments.

Increasing research suggests a close link between schizophrenia and cell death (Glantz et al., 2006; Yang and Xu, 2020), and the initial thorough examination of 12 different PCD modes in schizophrenia was achieved in this research. It was shown from the results that schizophrenia is most closely linked to Apoptosis, Ferroptosis, Autophagy, Entotic cell death, cell death associated with lysosomes, and Alkaliptosis (Jarskog, 2006; Sragovich et al., 2017; Feng et al., 2022). We evaluated the diagnostic value of PCD in SC patients by integrating bioinformatics analysis and machine learning methods. One of the most noteworthy discoveries is the identification of 10 pivotal candidate genes (DPF2, ATG7, GSK3A, TFDP2, ACVR1, CX3CR1, AP4M1, DEPDC5, NR4A2, and IKBKB).

ATG7 is a Protein Coding gene associated with Ferroptosis, Autophagy, and Entotic Cell Death. Spinocerebellar Ataxia, Autosomal Recessive 31, Fatty Liver Disease andNon-alcoholic 1 are the diseases caused by ATG7and this gene’s related pathways include Autophagy and antigen processing and presentation mediated by MHC Class I (Stelzer et al., 2016). Although the relationship between ATG7 and schizophrenia has yet to be studied, Genecards shows that this gene is significantly associated with neuronal abnormalities and mental illness, i.e., Neurodegeneration Caused by Brain Iron Accumulation, Huntington’s Disease, and Other Conditions.

GSK3A (Glycogen Synthase Kinase 3 Alpha) is a gene responsible for protein coding. Pancreatic cancer and hepatocellular carcinoma are two diseases linked to GSK3A. GSK3A is reported to be 80% lower in lymphocytes of patients with schizophrenia and is a regulatory enzyme of some neuronal proteins associated with schizophrenia abnormalities (Nadri et al., 2003). This discovery was confirmed by Stephen et al., who proposed GSK3A as a schizophrenia biomarker in blood identification (Glatt et al., 2005).

ACVR1 (Activin A Receptor Type 1) is a gene that codes for protein. Fibrodysplasia Ossificans Progressiva and Epicanthus are two diseases linked to ACVR1. This gene has been proved in genome-wide association research of schizophrenia by Lee et al. (2013) to be involved in rs1146031 to ACVR1 to mesoderm formation and activin binding potential pathways (p < 0.001, FDR = 0.032, 0.034). Class A comprising rhodopsin-like receptors includes CX3CR1 which is a Gi protein-coupled receptor (GPCR) with seven transmembrane domains (Imai et al., 1997). CX3CR1 (40 kDa) is made up of 355 amino acid residues that form an extracellular N-terminus, alternately arranged α-helical domains (TM1-TM7), intracellular (IL1-IL3) and extracellular (EL1-EL3) loops, and an intracellular C-terminus (Raucci et al., 2014). CX3CR1 levels were found downregulated in schizophrenia and may be associated with a depression-anxiety phenotype (Bergon et al., 2015; Chamera et al., 2021).

According to our KEGG analysis, candidate genes are primarily enriched in the NF-κB signaling pathway, which plays a critical role in the pathophysiology of schizophrenia. According to the study, PACER levels were significantly lower in schizophrenia patients than in healthy subjects. It has been demonstrated that CTCF induces the expression of this lncRNA. Therefore, the inhibitory NF-B complex is blocked by PACER, thereby increasing the expression of COX-2 (Krawczyk and Emerson, 2014). The pairwise correlations between the lncRNAs and genes revealed significant correlations between each pair, which further confirms their involvement in a specific signaling pathway, namely the NF-B pathway. A robust correlation was observed between NKILA/ADINR and NKILA / HNF1A-AS1, suggesting that these genes have a close functional connection (Safa et al., 2020).

The six most relevant drugs (Aflatoxin B1, Valproic Acid, Arsenic, Benzo(a)pyrene, epigallocatechin gallate and Nickel) were selected through the gene-drug interaction network. Valproic Acid (VPA), a branched short-chain fatty acid extracted from naturally occurring valeric acid, is a commonly used drug for bipolar disorder (McIntyre et al., 2020). VPA exerts its pharmacodynamic effects in a variety of ways: it acts on γ amino butyric acid (GABA) levels in the brain, blocks voltage-gated ion channels, and also acts as an HDAC inhibitor (Ghodke-Puranik et al., 2013). Tatiana et al. discovered that VPA prevented overactivity as well as latency inhibition and prepulse defects in Disc1-L100P mice, and that glia numbers were also increased in the subventricular zone in these mice, which VPA normalized (Lipina et al., 2012). Epigallocatechin gallate is an extract from green tea. Green tea, a centuries-old beverage, consists of antioxidant polyphenols, majorly epigallocatechin-3-gallate (EGCG), which inhibits nitric oxide synthase (NOS) and the production of cytokines (Ahmed et al., 2002; Singal et al., 2006). It also improves learning and memory in old rats and has antidepressant and anti-anxiety properties (Vignes et al., 2006; Kaur et al., 2008; Sattayasai et al., 2008). An eight-week, randomized, double-blind study on the effects of EGCG on schizophrenia and bipolar disorder discovered that EGCG could achieve some treatment effect on negative symptoms compared to placebo, but did not induce any notable effect on positive symptoms or inflammatory markers (Loftis et al., 2013), indicating that more research is needed on the efficacy of EGCG on positive symptoms of schizophrenia.

Limitations of this study: Although the diagnostic prediction model performed well in this study it was not further validated in combination with experiments; it could not be analyzed along with clinical information due to insufficient corresponding clinical correlation studies.

Our study systematically discovered 10 candidate hub genes (DPF2, ATG7, GSK3A, TFDP2, ACVR1, CX3CR1, AP4M1, DEPDC5, NR4A2, and IKBKB). A good diagnostic prediction model was established through comprehensive analysis in both the training (AUC 0.91, CI 0.95–0.86) and validation group (AUC 0.94, CI 1.00–0.85). Drugs that may be useful in the treatment of schizophrenia were also obtained (Valproic Acid, Epigallocatechin gallate).

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

YF and JS wrote the main manuscript text. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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