From organ replacement to functional restoration: A paradigm shift in liver failure therapy.

Abstract Liver transplantation has long been the definitive treatment for end-stage liver diseases, and yet its clinical use remains constrained by donor shortages, surgical risks, and the burden of lifelong immunosuppression. Emerging regenerative strategies, and particularly chemically induced liver progenitors (CLiPs), are reshaping this paradigm by enabling functional restoration rather than organ replacement. CLiP technology utilizes small-molecule-mediated partial reprogramming of mature hepatocytes into proliferative progenitor-like cells, which can be expanded and re-differentiated into functional hepatic lineages. This commentary discusses the conceptual shift from replacement to regeneration, it evaluates the clinical positioning of CLiP-based therapies, and it highlights key translational challenges. Rather than serving as a complete substitute for liver transplantation, such approaches may significantly reduce transplant demand by restoring critical hepatic function in selected patients.