The Pyroptosis-Related Signature Predicts Diagnosis and Indicates Immune Characteristic in Major Depressive Disorder

Pyroptosis is recently identified as an inflammatory form of programmed cell death. However, the roles of pyroptosis-related genes (PS genes) in major depressive disorder (MDD) remain unclear. This study developed a novel diagnostic model for MDD based on PS genes and explored the pathological mechanisms associated with pyroptosis. First, we obtained 23 PS genes that were differentially expressed between healthy controls and MDD cases from GSE98793 dataset. There were obvious variation in immune cell infiltration profiles and immune-related pathway enrichment between healthy controls and MDD cases. Then, a novel diagnostic model consisting of eight PS genes (GPER1, GZMA, HMGB1, IL1RN, NLRC4, NLRP3, UTS2, and CAPN1) for MDD was constructed by random forest (RF) and least absolute shrinkage and selection operator (LASSO) analyses. ROC analysis revealed that our model has good diagnostic performance, AUC = 0.795 (95% CI 0.721-0.868). Subsequently, the consensus clustering method based on 23 differentially expressed PS genes was constructed to divide all MDD cases into two distinct pyroptosis subtypes (cluster A and B) with different immune and biological characteristics. Principal component analysis (PCA) algorithm was performed to calculate the pyroptosis scores ("PS-scores") for each sample to quantify the pyroptosis regulation subtypes. The MDD patients in cluster B had higher "PS-scores" than those in cluster A. Furthermore, we also found that MDD patients in cluster B showed lower expression levels of 11 interferon (IFN)-α isoforms. In conclusion, pyroptosis may play an important role in MDD and can provide new insights into the diagnosis and underlying mechanisms of MDD.