Targeted Degradation of NRF2 Using an Oligonucleotide-PROTAC Overcomes Cancer Drug Resistance

Nuclear factor erythroid-2-related factor 2 (NRF2) is a master regulator of cellular redox homeostasis, orchestrating the expression of antioxidant enzymes and cytoprotective genes. While aberrant activation of NRF2 contributes to chemoresistance and tumor progression in various cancers, direct targeting of NRF2 has remained challenging due to its lack of enzymatic activity and ligand-binding domains. Here, we report a novel oligonucleotide-based proteolysis targeting chimera (Oligo-PROTAC) strategy for selective NRF2 degradation. These chimeras employ double-stranded oligonucleotides as recognition elements to recruit NRF2 and facilitate its ubiquitin-proteasome-mediated degradation. We designed a series of NRF2-targeting Oligo-PROTACs with distinct oligonucleotide sequences and linker architectures. Treatment with these constructs resulted in efficient NRF2 depletion, decreased transcriptional activity of downstream targets, elevated intracellular reactive oxygen species (ROS), and impaired proliferation of NRF2-active cancer cells. Co-treatment of NRF2-targeting Oligo-PROTACs with doxorubicin or erastin significantly enhanced the sensitivity of cancer cells to these agents, reducing their IC₅₀ values by approximately 50%. This sensitization effect was particularly pronounced in cancer cell lines previously characterized by resistance to these therapies. Furthermore, in vivo treatment with the NRF2-targeting Oligo-PROTAC induced significant tumor cell death, demonstrating the therapeutic potential of targeted NRF2 degradation in vivo. These findings highlight the promise of oligonucleotide-based targeted protein degradation as an innovative therapeutic strategy for traditionally undruggable targets such as NRF2.