Abstract
Prostate cancer (PCa) lacks precise diagnostic tools, necessitating noninvasive biomarkers. MicroRNAs (miRNAs) show promise due to fluid stability and oncogenic regulation. Using 2-sample Mendelian randomization (MR), we analyzed plasma miRNA expression quantitative trait loci (eQTLs) from discovery and validation cohorts. Cis-acting eQTLs served as instrumental variables, with causal effects assessed via inverse-variance weighted (IVW) and MR-Egger regression. Functional and survival analyses leveraged The Cancer Genome Atlas (TCGA)-PRAD data and bioinformatics tools. Five miRNAs (hsa-miR-127-3p, -370-3p, -125a-5p, -433-3p, -99b-5p) were inversely associated with PCa risk (IVW P < .05, FDR < 0.1). Two (hsa-miR-125a-5p/-99b-5p) were validated (OR = 0.992-0.9924, P < .05). Their 553 target genes included 9 survival-linked genes (e.g., FOXM1, BTG2), enriched in basement membrane organization, glutathione metabolism, and senescence. hsa-miR-127-3p was downregulated in PCa (fold change = 0.7, P < .001), with pan-cancer prognostic relevance. hsa-miR-125a-5p and -99b-5p are causal protective factors against PCa, modulating oncogenic pathways and survival. These miRNAs offer potential as noninvasive biomarkers and therapeutic targets, advancing precision oncology.