An FXR-dependent cellular program for Kupffer cell pool restoration fuels liver regeneration

Abstract Liver transplantation and partial hepatectomy represent the most effective therapeutic strategies for end-stage liver diseases. However, persistent donor organ shortages have intensified clinical interest in interventions that enhance liver regeneration. The farnesoid X receptor (FXR) and Kupffer cells both play crucial roles in liver regeneration. This study, therefore, aims to investigate whether FXR regulates liver regeneration by maintaining the homeostasis of Kupffer cells. In a 70% partial hepatectomy model, we observed robust activation and increased infiltration of T cells and Kupffer cells in the regenerating livers of wild-type (WT) mice. In contrast, although FXR-deficient (FXR −/− ) mice exhibited elevated baseline levels of both T cells and Kupffer cells in the liver, their regenerating livers showed markedly attenuated immune cell activation and reduced infiltration. During liver regeneration, the restoration of the Kupffer cell pool is achieved through the recruitment of circulating monocytes and the proliferation of resident Kupffer cells. Our data demonstrate that FXR deficiency impairs both the migration of circulating monocytes into the regenerating liver and the proliferation of resident Kupffer cells. Consequently, delayed liver regeneration in FXR −/− mice is likely due to impaired recovery of the Kupffer cell pool and altered M1/M2 polarization. Mechanistically, FXR promotes monocyte migration by targeting Ccr2 and enhances Kupffer cell proliferation via the CSF1/PI3K/Akt signaling pathway, thereby synergistically facilitating the restoration of Kupffer cell pool homeostasis during liver regeneration. Additionally, impaired monocyte recruitment in aged mice may contribute to reduced regenerative capacity with aging. Collectively, our findings demonstrate that homeostatic restoration and functional activation of Kupffer cells are critically governed by FXR. This mechanistic insight highlights FXR-Kupffer cells as a central therapeutic target for enhancing liver repair.