Biology subjects

Karamalakis, A. P.

Publications and source records attributed to Karamalakis, A. P..

2 recordsLinked to original sources

bioRxiv2026

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 (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.

cancer biology↗

bioRxiv2026

YAP disrupts bile acid homeostasis to drive cancer-associated cachexia

Cancer-associated cachexia is a severe metabolic syndrome marked by dramatic loss of adipose and muscle mass. Although preclinical models have advanced our understanding of cachexia, there are still no approved therapies due to the limited insights into the mechanisms underlying tissue wasting. Here, we utilise a YAP-driven model of liver cancer in zebrafish, which rapidly develops cachexia, to uncover an evolutionarily conserved role for bile acid disruption in the onset of cachexia. Spatial transcriptomic analysis revealed that YAP induces a bi-lineage cholangiocarcinoma phenotype, which was associated with bile acid dysregulation. Mechanistically, we establish that both bile acid synthesis (via CYP7A1) and signalling through the bile acid receptor TGR5 are essential for cachexia induction. Notably, we find that the promotion of bile acid excretion with odevixibat ameliorates cachexia. Together, our findings reveal an evolutionarily conserved mechanism by which YAP promotes cachexia and suggest a potential therapeutic strategy to treat the syndrome.

cancer biology↗