Ellagic Acid Enhances RSL3‐Induced Ferroptosis by Inhibiting the Nrf2/HO‐1 Signaling Pathway in Pancreatic Ductal Adenocarcinoma

Abstract

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) exhibits profound therapeutic resistance due to redox adaptation, particularly through Nrf2/HO‐1 pathway activation. Ferroptosis induction via GPX4 inhibitors (e.g., RSL3) is promising but limited by adaptive antioxidant responses. Ellagic acid (EA), a natural polyphenol, may overcome this resistance, yet its role in modulating ferroptosis remains unexplored. In vitro studies used KRAS‐mutant and KRAS wild‐type PDAC cell lines (PANC‐1, BxPC‐3) treated with EA, RSL3, or both. Ferroptosis markers (iron, lipid ROS, MDA, GPX4), viability assays, and pathway analyses (Keap1/Nrf2/HO‐1, p38 MAPK) were evaluated. In vivo, antitumor efficacy was assessed in PANC‐1 xenografts. EA synergized with RSL3, reducing viability in PDAC cells (p < 0.001) and suppressing tumor growth in vivo (p < 0.001). Combination therapy amplified ferroptotic markers as increased intracellular iron, MDA, and lipid ROS, versus RSL3 alone, while GPX4 expression decreased. Ferroptosis specificity was confirmed via Fer‐1 rescue. Mechanistically, EA activated p38 MAPK, suppressing Nrf2 nuclear translocation and HO‐1 expression. Keap1 upregulation further enhanced Nrf2 degradation. In vivo, EA + RSL3 downregulated Nrf2/HO‐1 and elevated phospho‐p38 in tumors along with the induction of ferroptosis. EA potentiates RSL3‐induced ferroptosis in PDAC by disrupting the p38/Nrf2/HO‐1 axis and elevating Keap1. This natural compound‐based strategy overcomes redox‐driven resistance, offering a translatable approach for PDAC models.