Prognostic significance of ferroptosis pathway gene signature and correlation with macrophage infiltration in cervical squamous cell carcinoma.

Background: Nuclear factor erythroid 2-related factor 2 (NFE2L2) plays a critical role in ferroptosis and biogenesis, however, its role in cervical squamous cell carcinoma (CESC) remains unknown. Therefore, in this study, we aimed to determine the role of NFE2L2 in CESC using multiomic analysis.

Methods: All raw data were downloaded from The Cancer Genome Atlas (TCGA) and further validated in our dataset. NFE2L2 mRNA expression and methylation data on CESC were examined using the Tumor Immune Estimation Resource (TIMER) and University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) database resources. NFE2L2 expression was examined in paraffin-embedded tissues from our cohort of 240 samples each of cancerous and non-cancerous tissues. Further, cervical cancer biopsies were genetically validated. TIMER and Tumor-Immune System Interactions Database (TISIDB) were used to analyze the correlation between NFE2L2 and cluster of differentiation 163 (CD163) with co-expressed genes in tumor-infiltrating immune cells.

Results: The mRNA and protein levels of NFE2L2 were lower in CESC tissues than they were in adjacent tissues. Importantly, a low NFE2L2 level correlated with poor prognosis in CESC patients. NFE2L2 was specifically expressed in tumor macrophages and correlated with the tumor immune landscape and poor prognosis in the cohort data. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analysis showed that co-expressed genes are mainly associated with multiple immune-related pathways. Furthermore, our data analysis revealed that NFE2L2 and macrophage CD163 expression levels were negatively correlated. Interestingly, we discovered multiple NFE2L2 binding sites in promoters of CD163.

Conclusion: This study confirmed the novel pyroptosis landscape in CESC, provided a role for NFE2L2 in the tumor microenvironment, and identified prognostic biomarkers for CESC and related immune infiltration.