Chronic liver disease (CLD) affects over one billion people globally and remains a leading cause of mortality, with liver transplantation as the sole curative option for end-stage liver disease. However, this life-saving procedure is limited by donor shortages, high costs, and long-term complications, underscoring the need for innovative therapeutic approaches. Here, I propose a paradigm shift in addressing CLD, focused on a novel strategy aimed at targeting liver sinusoidal endothelial cells (LSECs). We demonstrate the feasibility of LSEC reprogramming in a mouse model of a rare liver disease, and aim to (1) optimize the minimal effective dose for maximal therapeutic effect and (2) evaluate the therapy in mouse models of common forms of CLD.