PRDX4 expression potentially links redox adaptation to oncogenic signaling and tumor progression in pancreatic ductal adenocarcinoma.

Abstract

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive behavior, therapeutic resistance, and redox imbalance. Peroxiredoxin 4 (PRDX4), an endoplasmic reticulum-localized antioxidant enzyme, has been implicated in tumor progression, but its clinical significance and redox-associated role in PDAC remain unclear. METHODS: PRDX4 expression was assessed by immunohistochemistry in 128 resected PDAC specimens and correlated with clinicopathological features and disease-specific survival (DSS). Functional effects were examined in PRDX4-overexpressing PDAC cell lines. Intracellular reactive oxygen species (ROS) were evaluated under basal and oxidative stress conditions, with N-acetyl-l-cysteine (NAC) rescue. Signaling and redox-related proteins were analyzed by Western blotting. A PRDX4-transgenic mouse model was used to evaluate tumor growth, angiogenesis, and gemcitabine (GEM) responsiveness. RESULTS: High PRDX4 expression was associated with aggressive clinicopathological features and poor DSS. PRDX4 overexpression promoted cell proliferation and migration and reduced intracellular ROS levels. NAC treatment diminished ROS differences, supporting ROS-dependent redox modulation. PRDX4 overexpression was associated with increased ERK phosphorylation, suppressed JNK phosphorylation, increased total PI3K/AKT and p38 levels, reduced E-cadherin expression, and upregulation of NRF2 and HO-1. PRDX4 expression positively correlated with NRF2 and HO-1 in clinical specimens. In vivo, PRDX4 overexpression promoted tumor growth, increased microvessel density, and reduced GEM sensitivity. CONCLUSIONS: PRDX4 is associated with aggressive tumor behavior, redox adaptation, and might reduce gemcitabine responsiveness in PDAC in vivo, supporting its potential as a prognostic biomarker and a candidate molecule for future therapeutic investigation.

Key Findings

• High PRDX4 expression correlates with aggressive clinicopathological features and poor disease-specific survival in pancreatic ductal adenocarcinoma (PDAC).
• PRDX4 overexpression promotes PDAC cell proliferation and migration, reduces intracellular reactive oxygen species (ROS), and modulates redox-related signaling pathways including upregulation of NRF2 and HO-1.
• In vivo, PRDX4 overexpression enhances tumor growth, increases angiogenesis, and decreases gemcitabine sensitivity.

Clinical Significance

Citation

Liu Yao, Han Jia, Shioya Akihiroet al.. PRDX4 expression potentially links redox adaptation to oncogenic signaling and tumor progression in pancreatic ductal adenocarcinoma. Translational oncology. 2026-Jun-20.