Aberrant mitochondrial function and programmed cell death (PCD) were closely linked to the development of prostate cancer (PCa). In this study, prognostic genes related to mitochondria and PCD in PCa were explored through transcriptomic data, single-cell data, and Mendelian randomization (MR) analyses.

In this study, transcriptomic datasets, single-cell datasets, and genome-wide association study (GWAS) datasets were included from public databases. Firstly, genes co-expressed with mitochondria and PCD in PCa were selected based on the transcriptomic data. Subsequently, genes significantly causally linked to PCa were identified through MR analysis for further investigation. Prognostic genes were then selected using univariate Cox analysis and 10 algorithms, and a risk model was constructed to evaluate the prognostic performance of these genes. Subsequently, nomogram, mutation analysis, functional analysis, immune analysis, clinical feature correlation analysis, and drug sensitivity analysis were carried out. Prognostic gene functional analysis was subsequently conducted at the single-cell level. In addition, reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) was applied to verify the expression level of prognostic gene.

Prognostic genes identified in this study include PLK1, UBE2C, QSOX1, REXO2, CYP27A1, and TP63. A risk model utilizing these prognostic genes was developed to effectively forecast the survival outcomes of high- and low-risk cohorts. Significant correlations were observed between distinct immune cells and risk scores, such as a negative association between Keratinocytes, Sebocytes, and risk scores. At the single-cell level, the pivotal roles of prognostic genes in the developmental processes of key cells were observed. For instance, REXO2 exhibited an initial increase followed by a decrease over time in Epithelial cells. In the TCGA-PRAD and GSE70769 datasets, elevated levels of PLK1, UBE2C, and REXO2 were detected in the PCa group compared to the control group, while CYP27A1 and TP63 showed decreased expression in the PCa cohort. Meanwhile, expression of PLK1, UBE2C, and REXO2 were significantly decreased in PCa compared with the control group, while the opposite was observed for QSOX1, CYP27A1, and TP63.

Six prognostic genes (PLK1, UBE2C, QSOX1, REXO2, CYP27A1, and TP63) were identified, shedding light on their roles in the occurrence and prognosis of PCa, thereby offering new insights for clinical diagnosis and prognostic strategies for PCa.