Uterine corpus endometrial carcinoma (UCEC), a gynecologic cancer with the second highest incidence rate in women, is the main cause of death in female patients with cancers because of the high relapse rate (1, 2). UCEC has a low survival rate and poor prognosis (3–5). However, if diagnosed correctly in the early stage, 5-year survival rates up to 90% have been reported (6). A growing number of studies have shown that some patients in the same stage can exhibit different clinical outcomes and characteristics; therefore, an urgent need for increasingly valid and accurate methods to diagnose and treat patients with UCEC exists (7).

Pyroptosis is a newly discovered and confirmed mode of programmed cell death (8–10). Pyroptosis can be divided into classical and non-classical pathways. Pyroptosis relies mainly on inflammatory vesicles activating some proteins of the caspase family, namely, the pore-forming proteins gasdermin D (GSDMD) or gasdermin E (GSDME/DFNA5), causing cleavage, activation, and translocation of activated gasdermin proteins to the membrane, a site at which they form pores, cause cell swelling and cytoplasmic efflux, and eventually lead to cell membrane rupture (11). Pyroptosis is thought to contribute a dual role in tumorigenesis and progression via restraining tumorigenesis and progression and creating a microenvironment that feeds the cancer and accelerates its growth (12). As found in non-small cell lung cancer, the transcription factor, p53, impedes tumor progression by promoting pyroptosis (13). In previous studies addressing gastric cancer, a novel gene signature associated with pyroptosis has been identified as a predictor of prognosis (14). Chemotherapy-induced GSDME-mediated pyroptosis plays a positive prognostic role in the antitumor response in oral squamous cell carcinoma (15). However, the value of genes associated with pyroptosis in UCEC patients has not yet been explored.

In our study, pyroptosis-related genes were filtered out to explore their correlation with the occurrence and development of UCEC. A risk model was constructed via application of the bioinformatic and statistical analyses of data from UCEC patients. Moreover, we estimated its predictive value among patients with UCEC.

UCEC is the most frequently occurring gynecologic malignancy worldwide, and its mortality and morbidity rates are increasing (19). UCEC patients present similar clinical features, but they have different clinical outcomes due to molecular heterogeneity (20). Recently, several papers have reported that pyroptosis has a good diagnostic and predictive power as a biomarker in each type of UCEC (21, 22). In addition, pyroptosis has been reported to contribute a crucial effect to tumorigenesis and progression (23, 24). Therefore, a growing number of studies have focused on identifying the signature of pyroptosis to forecast survival and immunotherapeutic responses in UCEC.

Autophagy, pyroptosis, and other mechanisms have been proven to mediate the loss of cell viability (25). Pyroptosis plays a crucial role in a series of pathogenic processes (26, 27). The relationship between pyroptosis and a tumor is intricate with cell death both driving tumor progression and compromising antitumor immunity while inhibiting tumorigenesis (28). Yu et al. (29) found that γ-glutamyl hydrolase (GGH) expression levels were associated with Th2 cell expression and low-killer cell infiltration of CD56 bright cells, a process that could drive UCEC progression. Zheng et al. (30) found that NPAS2 could lead to UCEC via an increase in tumor immune cell infiltration. Liu et al. (31) developed and validated a Treg-related risk signature (TRRS) to assess the prognosis of UCEC and reflect the immune status of UCEC; this TRRS was capable of predicting the prognosis of UCEC patients that allowed for personalized treatment to be provided. After a rigorous review of the references, it was concluded that pyroptosis was related to the development and progression of inflammatory or malignant tumors.

In recent advances in medicine, immune checkpoint inhibitors have proven to be a key therapeutic measure for malignancies (32). Programmed death protein 1 (PD-1), PD-L1, PD-L2, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) are common immune checkpoints (33, 34). PD-L1 is extensively expressed throughout the body, especially in cancer cells and immune cells (3). In our prognostic model, quantification of immune checkpoints in different clusters revealed higher expression in UCEC patients than that in normal subjects and higher expression in cluster 1 patients than that in cluster 2, suggesting that UCEC patients and cluster 1 patients could probably benefit from immunotherapy. Subsequently, the samples were divided into high- and low-risk groups based on the median of the risk scores. Further exploring the potential correlation between pyroptosis-related genes and immune infiltration, the analysis suggested that the high-risk group was characterized by lower levels of immune cell infiltration (monocytes, resting mast cells). Furthermore, as our study found, the immune scores of the high-risk group were lower than those of the low-risk group, suggesting a potential difference in their immune environment.

UCEC patients always have poor survival clinical results, emphasizing the requirement for more credible biomarkers of long-term patient prognosis and therapy (35). In our study, 47 pyroptosis-related genes were identified to explore the prognostic function of pyroptosis-related genes. Forty-two pyroptosis-related genes were confirmed for their function in UCEC development and progression. Eight pyroptosis-related genes were used to establish pyroptosis-related gene models to predict the OS of UCEC patients. Among them, IRF2 was shown to trigger the activation of GSDMD by mediating pyroptosis (36). Inflammatory vesicle activation initiates focal death via recruitment of caspase-1. GSDMD, a caspase-1/11 substrate, contributed to the promotion of the formation of non-selective pores within the plasma membrane, thereby inducing pyroptosis, which in turn leads to cell swelling, rupture, and release of pro-inflammatory factors, for instance, HMGB1, ATP, and IL-1β (12, 37, 38). Recently, pyroptosis was found to be activated by different molecular mechanisms, in which GSDMB is the executioner, but not GSDMD (39). Meanwhile, GSDMD and GSDMB were differentially expressed in most tumors, and all evidence supported their involvement in the induction of the pyroptosis process in cancer, which also increased the predictive value of UCEC (40, 41). GPX4 was a classical selenoprotein with lipid peroxidation inhibitory properties, which belonged to the glutathione peroxidase family (42). GPX4 played a role in the induction of cell death in a variety of cancers (43–45). Guerriero et al. (46) showed that GPX4 inhibits macrophage pyroptosis in mice. For UCEC, it may be beneficial to increase GPX4 and thus inhibit pyroptosis. In this study, GPX4 expression levels were found to be reduced in the high-risk group. Given the role of GPX4 in pyroptosis, the development of inducers targeting GPX4 may reduce the incidence of UCEC associated with pyroptosis and thus improve patient survival. It has been previously reported that CHMP2A deficiency leads to the accumulation of autophagic vesicles and induces pyroptosis (47). However, its role in cancer has not been clearly studied to date. Our study showed that low expression of CHMP2A was associated with poor prognosis in UCEC patients, which suggested that inhibition of CHMP2A deletion could be a target for the treatment of UCEC. In addition, other pyroptosis-related genes were mentioned for the first time in UCEC.

The differences in OS between the high-risk and low-risk groups according to age and tumor G3 grading were analyzed, with better OS in the low-risk than that in the high-risk group, but no significant results in tumor G1 and G2 grading were found. ROC analysis revealed that this model outperformed a model based on conventional clinical characteristics for predicting survival in UCEC. The risk model based on eight pyroptosis-related genes associated with OS was quite accurate. In this study, the prognostic model that can validly predict the prognosis of endometrial cancer in patients was constructed using the genes related to pyroptosis as a starting point. In our study, we used several methods to determine this new model to ensure its optimality and rational use. These results provide insight into future studies of the processes and mechanisms by which pyroptosis-related genes affect UCEC onset, development, and prediction. Currently, limited progress in the study of pyroptosis has been made, and the relationship between UCEC and pyroptosis has not been investigated. Although this particular relationship was explored to some extent and a prognostic model from multiple perspectives was constructed and validated, some shortcomings and limitations in our study should be recognized. First, this study used retrospective data, which may have some heterogeneity among patients. Therefore, more prospective cohort studies in larger populations are needed to test the prognostic value of this risk model. Second, more extensive molecular experiments should be performed to demonstrate the function of pyroptosis-related genes. Therefore, clinical sample size will be expanded to attempt to demonstrate the accuracy of the prediction model through further external validation to probe the interaction between pyroptosis-related genes and UCEC.

In conclusion, our study investigated UCEC occurrence, development, and prognosis and may contribute to reveal the course and mechanism of pyroptosis correction.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

XH, YL, and FX have contributed to the design of the study, searching the related papers and extracting data, preparing figures, analysis and interpretation of the data, and drafting the article. JL, XY, and JX took part in searching the related papers and extracting data, preparing figures, and analysis and interpretation of data. All authors read and approved the final submitted article.

This study was supported by grants from the Guangdong Basic and Applied Basic Research Foundation (2020A1515011519), Science and Technology Special Fund Project of Guangdong Province (High-level Hospital Construction Project) (2021010303), (Shanfu [2021] No. 88), the “Dengfeng Project” for the construction of high-level hospitals in Guangdong Province–The First Affiliated Hospital of Shantou University Medical College Supporting Funding (2019-70), and the Medical Science and Technology Research Foundation of Guangdong Province (A2020430, A2021409).

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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