The Polymer Society of Korea

이예진 (서울대학교)

이강원 (서울대학교)

Nuclear factor erythroid-2-related factor 2 (NRF2) is a central regulator of cellular redox homeostasis; however, its aberrant activation contributes to chemoresistance and tumor progression and has remained challenging to target pharmacologically. Here, we describe an oligonucleotide-based proteolysis targeting chimera (Oligo-PROTAC) strategy for selective NRF2 degradation. These chimeras utilize double-stranded oligonucleotides as recognition elements to recruit NRF2 and promote its ubiquitin–proteasome-mediated degradation. NRF2-targeting Oligo-PROTACs effectively depleted NRF2, attenuated downstream transcriptional programs, increased intracellular reactive oxygen species, and suppressed proliferation of NRF2-active cancer cells. Co-treatment of NRF2-targeting Oligo-PROTACs with either doxorubicin or erastin resulted in synergistic cytotoxicity, reducing IC50 values by approximately 50%, with particularly pronounced effects in drug-resistant cancer cell lines.