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bioRxiv · 10.64898/2026.02.09.704724

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

Ong, A. J. S.·Wong, C. C.·Karamalakis, A. P.·Evason, K. J.·Brown, K. K.·Cox, A. G.
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Abstract

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. 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.

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Ong, A. J. S., Wong, C. C., Karamalakis, A. P., Evason, K. J., Brown, K. K., Cox, A. G.. 2026-02-11. NRF2 co-opts the SWI/SNF complex to drive liver cell plasticity. https://doi.org/10.64898/2026.02.09.704724

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