A study published in Nature (DOI: 10.1038/s41586-024-07465-2) investigates the acquisition of epithelial plasticity in human chronic liver disease. Researchers used single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients with different stages of metabolic dysfunction-associated steatotic liver disease (MASLD) to map cellular changes during disease progression. They combined these data with advanced 3D imaging to reveal profound changes in liver architecture, including loss of hepatocyte zonation and reorganization of the biliary tree. The study found that hepatocytes and cholangiocytes can transdifferentiate into each other without the involvement of adult stem cells or developmental progenitors. Functional validations using cholangiocyte organoids confirmed the role of the PI3K-AKT-mTOR pathway in this process, linking it to insulin signaling. The findings suggest that chronic liver injury creates an environment that induces cellular plasticity, which could have therapeutic implications for chronic liver diseases. The study also identified factors associated with transdifferentiation, including SOX4, KRT23, KLF4, and NCAM1. The PI3K-AKT-mTOR pathway was shown to regulate cholangiocyte-to-hepatocyte plasticity, with insulin resistance playing a key role in this process. The study highlights the complex interplay between different signaling pathways in the liver, including the YAP-TAZ pathway, which may limit cholangiocyte plasticity. The research provides insights into the mechanisms of liver regeneration and disease progression, emphasizing the importance of understanding cellular plasticity in chronic liver diseases.A study published in Nature (DOI: 10.1038/s41586-024-07465-2) investigates the acquisition of epithelial plasticity in human chronic liver disease. Researchers used single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients with different stages of metabolic dysfunction-associated steatotic liver disease (MASLD) to map cellular changes during disease progression. They combined these data with advanced 3D imaging to reveal profound changes in liver architecture, including loss of hepatocyte zonation and reorganization of the biliary tree. The study found that hepatocytes and cholangiocytes can transdifferentiate into each other without the involvement of adult stem cells or developmental progenitors. Functional validations using cholangiocyte organoids confirmed the role of the PI3K-AKT-mTOR pathway in this process, linking it to insulin signaling. The findings suggest that chronic liver injury creates an environment that induces cellular plasticity, which could have therapeutic implications for chronic liver diseases. The study also identified factors associated with transdifferentiation, including SOX4, KRT23, KLF4, and NCAM1. The PI3K-AKT-mTOR pathway was shown to regulate cholangiocyte-to-hepatocyte plasticity, with insulin resistance playing a key role in this process. The study highlights the complex interplay between different signaling pathways in the liver, including the YAP-TAZ pathway, which may limit cholangiocyte plasticity. The research provides insights into the mechanisms of liver regeneration and disease progression, emphasizing the importance of understanding cellular plasticity in chronic liver diseases.