Hepatocyte transplantation represents a promising alternative to whole-organ liver transplantation for chronic liver fibrosis, yet poor engraftment and rapid functional decline limit its clinical success. While three-dimensional (3D) hepatocyte spheroids improve cell quality, the mechanisms sustaining their lineage-specific function remain unclear. In this study, we investigated the therapeutic efficacy of spheroids and the molecular pathways governing their identity. Compared to single cells, spheroids exhibited elevated hepatic gene expression, reduced apoptosis, and a distinctive Unfolded Protein Response (UPR) profile characterized by robust adaptive XBP1s signaling and CHOP suppression. Spheroid organization triggers a STAT3-XBP1s signaling axis that regulates lineage fidelity. Furthermore, the quiescent state inherent to the 3D structure enhances survival by downregulating eIF2 signaling, thereby suppressing pro-apoptotic CHOP expression and maximizing graft survival. In vivo validation in a CCl₄-induced fibrosis model showed that intraportal spheroid transplantation resulted in prolonged cell retention and significant attenuation of fibrosis compared to single-cell transplantation. Collectively, UPR-mediated reinforcement of hepatocyte identity and survival is fundamental to the efficacy of spheroid grafts, supporting intraportal spheroid transplantation as a potent therapeutic strategy for chronic liver fibrosis.