Liquid Biopsy-Derived microRNAs in Pancreatic Ductal Adenocarcinoma: Matrix-Specific Evidence and Translational Challenges.

MicroRNAs are small noncoding RNA molecules that regulate gene expression at the post-transcriptional level and play a key role in cancer development, progression, and response to therapy. Their relative stability in biological fluids and disease-associated expression patterns have positioned microRNAs as promising candidates for non-invasive cancer biomarkers. Liquid biopsy enables the detection of circulating and fluid-derived microRNAs in a range of biological materials, including blood, urine, saliva, stool, pancreatic cyst fluid, and bile, offering a minimally invasive complement to tissue-based diagnostics. This approach is particularly relevant in pancreatic ductal adenocarcinoma, a malignancy with high mortality driven largely by late diagnosis, aggressive disease course, and limited opportunities for curative treatment. This review summarizes current evidence on microRNA-based liquid biopsy approaches in this cancer, with a focus on diagnostic, prognostic, and predictive relevance. Serum and plasma remain the most extensively studied sources, while urine-based microRNA profiling has shown relatively consistent diagnostic performance across available studies, including in early-stage disease. Pancreatic cyst fluid and bile offer more lesion-proximal molecular information but are limited to selected clinical scenarios because of invasive sampling requirements. In contrast, salivary microRNA signatures show greater variability and lower reproducibility across studies. Overall, liquid biopsy based on microRNA analysis shows promise as a complementary tool for pancreatic ductal adenocarcinoma detection and risk stratification. However, substantial methodological heterogeneity and limited cross-study reproducibility currently limit clinical translation, underscoring the need for standardized workflows and prospective validation of clinically relevant microRNA panels.