Background: Ferroptosis, a recently discovered form of cell death, whose role in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) has not been well disclosed. To improve our understanding of the differences in tumor progression and therapeutic effects between BCC and SCC, and to find potential therapeutic targets, this study systematically analyzed ferroptosis-related genes (FRGs) and their associated local immune cytolytic activity (LICA) and tumor microenvironment (TME) metabolic function differences.

Methods: Two bulk RNA-seq datasets, GSE7553 and GSE125285, from the Gene Expression Omnibus database were compared within and between groups to screen for common differentially expressed genes (DEGs) for enrichment analysis. The currently recognized FRGs in DEGs gene set were selected as the targets to analyze their correlation and difference in LICA and TME metabolic functions. And validated using immune cell populations from another single-cell RNA-seq (scRNA-seq) dataset (GSE123813) to accurately understand the difference in LICA. All of the gene sets for functional enrichment analysis comes from published results and MSigDB database.

Results: Ten FRGs were used to further analyze the differences in LICA and TME metabolic functions between BCC and SCC. In the SCC samples, LICA (e.g. Treg, CCR, Cytolytic activity, etc.) and TME metabolic functions (e.g. lipid and energy, etc.) were significantly related to ferroptosis genes (e.g. SLC1A5, CD44, NQO1, HMOX1 and STEAP3), and the ferroptosis potential index were also significantly higher than that in the BCC samples. Finally, based on these ten FRGs and related enrichment results, we postulated a model of NQO1 homeostasis regulated by FRGs during induction of ferroptosis in SCC.

Conclusions: The results showed that three FRGs, SLC1A5, CD44 and NQO1, have significant potential in targeted therapies for SCC chemotherapy resistance. And two FRGs, STEAP3 and HMOX1, formed a synergistic effect on the occurrence of ferroptosis in tumor cells. Our findings can be used as the main research materials for metastasis and chemotherapy resistance in SCC patients.