Fatty acid metabolism heterogeneity in prostate cancer unveils prognostic biomarkers and immune crosstalk

Background

Fatty acid metabolism (FAM) is critical in prostate cancer (PCa), but few studies have explored its single-cell mechanisms. We analyzed single-cell and bulk transcriptome data from PCa patients to uncover FAM's role and identify potential therapeutic targets.

Methods

Single-cell RNA sequencing identified ELOVL5, SCD, and FADS2 as key FAM genes. FAM scores were calculated using the “AUCell” algorithm and a gene list from the molecular signatures database. FAM scores in each cell type were compared between benign and cancerous samples. In three significant cell types, cells were grouped into high- and low-FAM categories based on median scores, and differentially expressed genes (DEGs) between groups were identified. DEGs were analyzed in bulk RNA sequencing to identify prognostic genes, validated by RT-qPCR. Cell interactions were explored using the “CellChat” algorithm to identify FAM-related communications.

Results

Three key FAM genes—ELOVL5, SCD, and FADS2—were differentially expressed between benign and cancerous samples. High FAM scores were observed in cancer cells and monocytes but lower in T cells. Cancer cells with high FAM scores showed increased stemness and copy number variations. In T cells and monocytes, FAM scores correlated with differentiation. CD226 and NECTIN2 were key interactions in the high-FAM group. Twelve FAM-related genes were identified as prognostic factors, validated by RT-qPCR.

Conclusions

FAM levels are elevated in prostate adenocarcinomas, particularly in cancer cells, monocytes, and T cells. High FAM scores correlate with stemness and genetic instability in cancer cells, while indicating increased differentiation in monocytes and T cells. CD226 and NECTIN2 were key interactions in the high-FAM group, suggesting FAM's role in NECTIN2–CD226 interactions and its potential link to the NECTIN2–TIGIT immune checkpoint axis.