This study investigates the acquisition of epithelial plasticity in human chronic liver disease, specifically metabolic dysfunction-associated steatotic liver disease (MASLD). Using single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients at different stages of MASLD, the researchers established a cellular map of the liver during disease progression. They combined these single-cell-level data with advanced 3D imaging to reveal significant changes in liver architecture, including the loss of hepatocyte zonation and reorganization of the biliary tree. The study also uncovered transdifferentiation events between hepatocytes and cholangiocytes without the presence of adult stem cells or developmental progenitor activation. Detailed analyses and functional validations using cholangiocyte organoids confirmed the importance of the PI3K-AKT-mTOR pathway in this process, connecting the acquisition of plasticity to insulin signaling. The findings suggest that chronic injury creates an environment that induces cellular plasticity in human organs, and understanding these mechanisms could open new therapeutic avenues for managing chronic diseases.This study investigates the acquisition of epithelial plasticity in human chronic liver disease, specifically metabolic dysfunction-associated steatotic liver disease (MASLD). Using single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients at different stages of MASLD, the researchers established a cellular map of the liver during disease progression. They combined these single-cell-level data with advanced 3D imaging to reveal significant changes in liver architecture, including the loss of hepatocyte zonation and reorganization of the biliary tree. The study also uncovered transdifferentiation events between hepatocytes and cholangiocytes without the presence of adult stem cells or developmental progenitor activation. Detailed analyses and functional validations using cholangiocyte organoids confirmed the importance of the PI3K-AKT-mTOR pathway in this process, connecting the acquisition of plasticity to insulin signaling. The findings suggest that chronic injury creates an environment that induces cellular plasticity in human organs, and understanding these mechanisms could open new therapeutic avenues for managing chronic diseases.