Dysregulation of ferroptosis-related genes and the ACSL4-mediated ferroptosis-PD-L1 axis in prostate cancer pathogenesis

Prostate cancer (PCa) is a major cause of morbidity and mortality worldwide. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a crucial mechanism in various cancers, including PCa. This study focused on two interrelated aspects of ferroptosis in PCa. Firstly, it sought to determine whether ferroptosis-related genes are dysregulated in PCa and correlate with disease subtypes and prognosis. Secondly, it aimed to investigate whether the ACSL4/PD-L1 axis mediates crosstalk between ferroptosis and the immune microenvironment. Using TCGA data, we identified 1019 differentially expressed genes (DEGs) between PCa and normal tissues, with the ferroptosis pathway prominently highlighted. Key ferroptosis genes exhibited altered expression profiles in PCa, suggesting their involvement in PCa pathogenesis. By constructing correlation networks, we revealed coordinated regulatory interactions between these genes in PCa. To better understand the implications of ferroptosis in PCa, we performed subtype analysis of PCa patients based on ferroptosis gene expression, identifying two stable subtypes. Lasso-Cox regression analysis further stratified patients into high and low-risk groups, which exhibited significant prognostic differences. Additionally, we explored the relationship between PD-L1, ferroptosis, and the immune microenvironment. PD-L1 expression was significantly lower in PCa tissues compared to normal tissues and varied across subtypes. It correlated strongly with ferroptosis-related genes ACSL4 and TFRC. Single-cell RNA sequencing revealed ACSL4 is predominantly expressed in fibroblasts within the PCa tumor microenvironment. Functional assays confirmed that ACSL4 positively regulated PD-L1 and that ferroptosis inhibition abrogates this regulatory effect. These findings highlight the complex interplay between ferroptosis, immune modulation, and prognosis in PCa, providing insights into potential therapeutic strategies that target ferroptosis-related pathways and immune checkpoint regulation.