[1PS-098]
우수논문발표상 응모자Targeted Degradation of NRF2 Transcription Factor by dNRF2 Oligonucleotide PROTAC Enhances Sensitivity of Cancer Redox Stress
발표자이예진 (서울대학교)
연구책임자이강원 (서울대학교)
Abstract
Nuclear factor erythroid-2-related factor 2 (NRF2) is a master regulator of redox homeostasis, activating antioxidant and cytoprotective genes. However, its aberrant activation drives chemoresistance and tumor progression, while direct inhibition remains challenging due to its non-enzymatic, non-ligandable nature. Here, we introduce an oligonucleotide-based proteolysis targeting chimera (Oligo-PROTAC) platform for selective NRF2 degradation. These constructs utilize double-stranded oligonucleotides to bind NRF2 and induce ubiquitin-proteasome-mediated degradation. NRF2-targeting Oligo-PROTACs effectively reduced NRF2 levels, suppressed downstream gene expression, elevated intracellular ROS, and inhibited proliferation in NRF2-hyperactive cancer cells. Notably, co-treatment with doxorubicin or erastin produced synergistic cytotoxicity, lowering IC50 values by ~50%, especially in drug-resistant lines. These findings support oligonucleotide-based targeted protein degradation as a viable therapeutic strategy for addressing otherwise undruggable oncogenic regulators.