Ovarian cancer (OC) is a highly malignant gynecological tumor with a poor prognosis, characterized by high recurrence and mortality rates. Current treatments, primarily surgery and platinum-based chemotherapies, have shown limited improvement in 5-year survival rates, highlighting the urgent need for novel therapeutic targets and prognostic models. Pyroptosis, an inflammatory form of programmed cell death, has emerged as a potential area of investigation in cancer. This process involves cellular swelling, vesicle formation, pore formation in the cell membrane, and the release of cell contents, triggering inflammatory responses. The gasdermin family is central to pyroptosis execution. While pyroptosis's role in combating infection is established, its involvement in tumor development and the immune microenvironment is increasingly recognized. Some studies suggest a dual role: promoting tumorigenesis through inflammatory factors, while also offering a potential therapeutic target by inducing tumor cell pyroptosis. Existing research indicates pyroptosis's influence on the tumor immune microenvironment, with elevated GSDMD expression correlating with decreased CD8+ T lymphocyte activity. This study aimed to systematically investigate the expression levels of pyroptosis-related genes in OC and normal ovarian tissues, assess their prognostic value, and explore their correlation with the tumor immune microenvironment.

The literature review section summarizes existing knowledge regarding pyroptosis's role in cancer. Studies highlighting pyroptosis's dual role in tumor development and therapeutic mechanisms are cited. Specific examples of how pyroptosis-related genes, particularly gasdermin family members, contribute to the process are discussed, along with the connections between pyroptosis and immune responses. The review sets the stage for this study by emphasizing the limited understanding of pyroptosis's specific functions in ovarian cancer.

The study utilized data from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases to identify differentially expressed genes (DEGs) related to pyroptosis in ovarian cancer. A total of 88 normal and 379 tumor samples were analyzed, resulting in the identification of 31 DEGs. Protein-protein interaction (PPI) analysis was performed to explore the interactions among these genes. Consensus clustering analysis was used to classify OC patients based on the expression of these DEGs. Univariate Cox regression analysis was used to screen for survival-related genes, followed by LASSO Cox regression analysis to construct a prognostic gene signature. The resulting 7-gene signature was used to calculate a risk score for each patient, classifying them into low- and high-risk groups. Kaplan-Meier analysis was employed to compare the overall survival (OS) times between the groups. The model was validated using an independent Gene Expression Omnibus (GEO) cohort (GSE140802). Univariate and multivariate Cox regression analyses were conducted to assess the independent prognostic value of the risk score, adjusting for other clinical factors. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to explore the biological functions and pathways associated with the DEGs. Single-sample gene set enrichment analysis (ssGSEA) was used to compare the immune cell infiltration and immune pathway activity between low- and high-risk groups in both cohorts.

The study identified 31 differentially expressed pyroptosis-related genes in ovarian cancer tissues compared to normal tissues. A 7-gene signature (AIM2, PLCG1, ELANE, PIVK, CASP3, CASP6, and GSDMA) was developed using LASSO Cox regression and validated in an independent cohort. This signature effectively stratified patients into low- and high-risk groups, with the high-risk group exhibiting significantly shorter overall survival times (P<0.001 in TCGA and P=0.014 in GEO). The risk score was identified as an independent prognostic factor in both cohorts. Functional enrichment analyses revealed that the differentially expressed genes between the risk groups were significantly enriched in immune-related pathways. The high-risk group demonstrated lower infiltration of various immune cells, including CD8+ T cells, neutrophils, NK cells, and T helper cells, and decreased activity in several immune-related pathways, suggesting an impaired immune response in these patients.

The findings support the hypothesis that pyroptosis-related genes are significantly involved in ovarian cancer prognosis. The 7-gene signature offers a novel and robust tool for predicting patient survival. The association of the high-risk group with decreased immune cell infiltration and pathway activity highlights the interplay between pyroptosis and the tumor immune microenvironment. Individual genes within the signature, such as AIM2, PLCG1, ELANE, and others, have known roles in inflammation and cell death pathways, but their specific roles in OC pyroptosis require further investigation. The study also notes some unexpected observations, such as the higher proportion of Treg cells in the low-risk group, which may warrant further research into Treg cell subtypes in OC. The overall decreased immune activity in the high-risk group suggests potential therapeutic strategies targeting the immune microenvironment.

This study establishes a novel 7-gene pyroptosis-related signature for predicting ovarian cancer prognosis. The signature's independent prognostic value and its association with immune dysfunction highlight the importance of pyroptosis in OC. Future studies could focus on the detailed mechanisms of action of these genes in OC pyroptosis, exploring therapeutic interventions targeting these pathways to improve patient outcomes. Further investigation into the specific subtypes of Treg cells and their functional roles in the context of pyroptosis is also warranted.

The study's reliance on publicly available datasets limits the ability to control for all potential confounding factors. Further validation in larger, independent cohorts, and functional studies to elucidate the precise roles of these genes in OC pyroptosis are needed. The study mainly focuses on mRNA expression levels, and future studies could incorporate proteomic data to provide a more comprehensive understanding of the pyroptosis-related gene signature in ovarian cancer.