Topoisomerase 1 initiates biliary-derived liver regeneration through the Dnmt1-p53 axis.

In end-stage liver disease, impaired hepatocyte proliferation prevents regeneration. Biliary epithelial cell transdifferentiation thus becomes a critical alternative for liver repair, yet its efficiency remains low in mammals. Elucidating the initiation mechanisms of this process may unlock novel therapeutic targets for end-stage liver disease treatment. By leveraging the zebrafish severe liver injury model and its transparency, as well as the availability of small-molecule research, we identified that topoisomerase 1 (Top1) is essential for the initiation of biliary-derived liver regeneration. Top1 upregulation occurred early after liver injury. Moreover, genetic knockout (top1 mutants) or pharmacological inhibition (topotecan) impeded liver regeneration by suppressing cholangiocyte dedifferentiation, promoting cell apoptosis, and blocking the redifferentiation of bipotential progenitor cells into hepatocytes and cholangiocytes. Mechanistically, Top1 activates DNA methyltransferase 1 (Dnmt1) in cholangiocytes, thereby depressing p53 during dedifferentiation, which subsequently maintains the activity of mTOR signalling in cholangiocytes to trigger regeneration initiation. These findings suggest that the Top1-Dnmt1-p53 axis orchestrates the initiation of biliary-driven liver regeneration.