Poster Presentation 38th Lorne Cancer Conference 2026

NRF2 co-opts the SWI/SNF complex to drive liver cell plasticity (#231)

Athena Jessica S Ong 1 2 , Anthony P Karamalakis 1 , Kimberley J Evason 3 4 , Kristin K Brown 1 2 5 , Andrew G Cox 1 2 5
  1. Peter MacCallum Cancer Center, Carlton, VICTORIA, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  3. Department of Pathology, University of Utah, Salt Lake City, UT, USA
  4. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
  5. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia

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 (NRF2T80K), 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. Finally, we show that NRF2-driven transdifferentiation can be suppressed by a selective inhibitor of Brahma-related gene 1/Brahma (BRG1/BRM) within the Switch/sucrose non-fermentable (SWI/SNF) complex. 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.