Identification of genetically predicted protein biomarkers and drug targets for prostate cancer via Mendelian randomization

The proteomics plays a crucial role in identifying therapeutic targets. In this study, we utilized Weighted Gene Co‐expression Network Analysis (WGCNA) and Mendelian Randomization (MR) to identify potential protein biomarkers and therapeutic targets for prostate cancer (PCa). To select PCa‐related genes, we constructed a WGCNA using genetic data from The Cancer Genome Atlas (502 cases and 52 controls). We sourced expression quantitative trait locus (eQTL) data from the eQTLGen consortium database and obtained outcome data from the MR Base database (3269 cases and 459,664 controls). Subsequently, MR and colocalization analyses were performed to validate the causal relationships of the candidate proteins. Additionally, we conducted immune infiltration analysis, gene set enrichment analysis, gene set variation analysis, drug sensitivity analysis, Nomogram model construction, transcriptional regulatory analysis, correlation analysis with PCa‐regulated proteins, single‐cell sequencing, and spatial transcriptomics analysis to detect specific cell types with enriched expression and consider potential therapeutic targets. The results of our study revealed that five genetically predicted proteins were associated with PCa risk. Decreased levels of one protein (thrombomodulin [THBD]) and increased levels of four proteins (dystonin [DST], interferon‐alpha‐inducible protein 27 like 2 [IFI27L2], oxysterol‐binding protein‐related protein 10 [OSBPL10], and protein phosphatase 1 regulatory inhibitor subunit 14A [PPP1R14A]) were found to be linked to increased PCa risk. These protein‐encoding genes are distributed across different types of cells in PCa tissue, indicating their potential as therapeutic targets for PCa. Our study identified several protein biomarkers associated with PCa risk, providing new insights into the etiology of PCa and offering promising targets for the development of PCa screening biomarkers and therapeutic drugs.