Buthelezi, Sindisiwe GElebo, NNaicker, PMokoena, Rethabile JDubazana, SGovender, Ireshyn IMamputha, SiphoEllero, AStoychev, SMazibuko, J2026-08-182026-08-182026-081535-38931535-3907https://doi.org/10.1021/acs.jproteome.6c00172http://hdl.handle.net/10204/14893Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer and was ranked among the top seven leading causes of cancer-related deaths in South Africa in 2020. Highlighting the urgent need for ongoing research to identify reliable biomarkers to improve clinical outcomes. This study compared the plasma proteomes of patients with PDAC, those with benign biliary pathologies (BBP), and healthy controls (HC). We used Mag-Net, a magnetic-bead-based method that enriches membrane-bound vesicles. Comparative analyses identified distinct and overlapping dysregulated proteins between PDAC, BBP, and HC. PDAC showed enrichment for epithelial-mesenchymal transition, complement activation, hypoxia, glycolysis, and extracellular matrix remodeling pathways, consistent with aggressive tumor biology. Proteins including SPP1, THBS2, PTX3, FBLN2, SDC1, CTSS, and VCAN were significantly increased in PDAC, with LRG1 showing the strongest association with disease severity. Proteins, namely GPNMB, H4C1, SAA1, and CCDC47, demonstrated progressive upregulation across disease comparisons, suggesting potential relevance to disease progression. These findings demonstrate that plasma proteomics provides discriminatory molecular insights and supports the development of population-relevant biomarker panels. While several candidate proteins show promise for inclusion in multianalyte panels, further validation in larger cohorts is necessary to establish their diagnostic and translational utility for early detection, risk stratification, and improved differential diagnosis of PDAC.FulltextenPancreatic ductal adenocarcinomaPDACBiomarkersPlasmaExtracellular vesiclesMag-Net ProteomicsArticlen/a