Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with dysregulated lipid metabolism emerging as a key driver of tumor aggressiveness. Cancer cells rewire their metabolic pathways to sustain rapid proliferation, and increased de novo fatty acid synthesis is a hallmark of PCa. Elevated fatty acid levels not only provide energy but also serve as building blocks for membranes and signaling molecules, facilitating tumor growth and metastasis. Despite advances in understanding metabolic reprogramming, the specific contributions of lipid metabolism genes in different immune cell populations within the tumor microenvironment remain unclear. This study investigates the expression patterns of key lipid metabolism genes—ACSL1, ACSL4, MBOAT7, and SLC25A17—in prostate cancer patients using single-cell RNA sequencing (scRNA-seq) to uncover their potential roles in disease progression.

Peripheral blood mononuclear cells (PBMCs) were isolated from four patients with histologically confirmed PCa using Ficoll gradient centrifugation and cryopreserved. Healthy control data were obtained from publicly available datasets. scRNA-seq was performed using the 10x Genomics Chromium X platform (Next GEM Single Cell 3′ Kit v3.1). Raw sequencing data were processed with Cell Ranger (v7.1.0), and downstream analysis was performed in R (v4.3.3) using the Seurat package (v5.1.0). Dimensionality reduction was achieved via UMAP, and cell clustering was performed using the FindNeighbors and FindClusters functions. Differential gene expression analysis was conducted with FindMarkers, and pathway enrichment was assessed using Enrichr (GO Biological Process).

Comparative analysis revealed distinct expression patterns of lipid metabolism genes in PCa patients versus healthy controls (Fig.1):  ACSL1 gene exhibited the strongest upregulation in monocytes, with moderate expression in dendritic cells, ACSL4 was expressed in both groups but significantly elevated in PCa monocytes and T-cells.  MBOAT7 and SLC25A17 showed variable expression across cell  and was not statistically significant.Notably, ACSL1’s pronounced expression in monocytes suggests a potential role in modulating immune responses within the tumor microenvironment.

Increased fatty acid metabolism supports PCa progression by fueling energy demands and membrane biosynthesis. The overexpression of ACSL1 in monocytes aligns with its known role in inflammation and foam cell formation, indicating a possible contribution to macrophage polarization and tumor-associated immunosuppression. Meanwhile, ACSL4 upregulation correlates with PCa aggressiveness, consistent with its involvement in ferroptosis resistance and metastatic potential . These findings highlight lipid metabolism as a critical node in PCa biology, with immune cell-specific alterations potentially shaping disease outcomes.

This study identifies ACSL1 and ACSL4 as key regulators of lipid metabolism in prostate cancer, particularly within monocytes and T-cells. The overexpression of these genes may drive tumor progression by altering immune cell function and promoting a protumorigenic microenvironment. Targeting fatty acid metabolism in specific immune subsets could offer a novel therapeutic strategy for PCa. Further validation in larger cohorts and functional studies will clarify their mechanistic roles and clinical relevance.