NRF2 co-opts the SWI/SNF complex to drive liver cell plasticity

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a role in the regulation of redox homeostasis and cellular metabolism. Activating mutations in the NRF2 pathway have been identified in approximately 15% of liver cancer patients. However, the mechanisms by which NRF2 promotes liver tumorigenesis are poorly understood. Employing a transgenic zebrafish model with hepatocyte-specific, inducible expression of a clinically relevant constitutively active NRF2 mutant (NRF2 ^T80K ), we show that constitutive activation of NRF2 drives hepatocyte to cholangiocyte transdifferentiation. Importantly, we demonstrate that NRF2 affects liver cell plasticity in a cell-autonomous, evolutionarily conserved, and reversible manner. Utilizing an epigenetic-focused chemical screen, the BRG1/BRM inhibitor FHD-286 was identified as a potent suppressor of NRF2-driven transdifferentiation. Overall, our study reveals a novel role for NRF2 in the regulation of liver cell plasticity during tumour initiation and identifies a therapeutic approach to overcome the oncogenic activity of NRF2.