Plasma proteome-based integrated mendelian randomization and multi-omics analysis identifies potential diagnostic biomarkers and therapeutic targets for prostate cancer

Background: Prostate cancer (PCa) is a major cause of cancer-related deaths in men, with challenges in early detection and effective treatment. Plasma proteins have emerged as promising diagnostic biomarkers and therapeutic due to their accessibility and reflection of tumor-related systemic changes. Methods: We performed a Mendelian randomization (MR) analysis to identify causal plasma proteins associated with PCa. Multi-omics data, including bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics, were integrated to explore molecular, cellular, and spatial expression patterns. Functional enrichment analysis (Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG)), diagnostic receiver operating characteristic (ROC) analysis, immune infiltration analysis, and molecular docking were conducted to elucidate their biological roles and therapeutic potential. Results: MR analysis identified 66 plasma proteins associated with PCa, highlighting their roles in extracellular matrix remodeling and inflammation. Multi-omics integration revealed four key biomarkers (transforming growth factor beta 3 (TGFB3), insulin-like growth factor binding protein 6 (IGFBP6), Golgi membrane protein 1 (GOLM1), and serpin family F member 1 (SERPINF1)) with distinct spatial expression patterns and links to tumor progression and immune modulation. TGFB3, IGFBP6, and SERPINF1 correlated positively with immune infiltration and checkpoints, while GOLM1 showed negative correlations. A combined diagnostic model achieved excellent accuracy (area under the curve (AUC) = 0.911). Functional enrichment connected these factors to pathways like Suppressor of Mothers Against Decapentaplegic (SMAD) signaling and Wingless/Integrated (Wnt) signaling. Small molecule screening and molecular docking identified diethylstilbestrol as a therapeutic candidate targeting TGFB3 and IGFBP6. Conclusions: Our findings provide novel insights into the molecular mechanisms of PCa and highlight promising diagnostic and therapeutic targets. Further experimental validation and clinical studies are needed to confirm these results and assess their translational potential.

Prostate cancer; Plasma proteome; Mendelian randomization; Multi-omics integration; Diagnostic biomarkers; Therapeutic targets

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