The research, led by Wenling Ye, Yang Zhao, and Fengling Wang under the direction of corresponding authors Wei-Dong Chen and Yan-Dong Wang, focused on the farnesoid X receptor, or FXR, a ligand-activated transcription factor expressed abundantly in the liver and intestine. FXR has long been recognized as a master regulator of bile acid homeostasis, lipid metabolism, and glucose control, and several FXR agonists have already entered clinical development for cholestatic liver disease and non-alcoholic steatohepatitis. The new work adds an unexpected dimension to this receptor’s portfolio: it appears to govern how the liver rebuilds its resident population of macrophages, the Kupffer cells, after surgical injury.

Kupffer cells are the liver’s resident sentinels, embedded in the sinusoidal blood vessels that perfuse the organ. They clear circulating debris and pathogens, but during regeneration they do something equally important: they broadcast the inflammatory and growth-promoting signals that push hepatocytes out of their quiescent state and into the cell cycle. Because these cells are consumed and reprogrammed as regeneration proceeds, the liver must continuously replenish its Kupffer cell pool from two sources. The first is local, the proliferation of resident Kupffer cells that survived the initial insult. The second is systemic, the recruitment of monocytes circulating in the bloodstream, which home to the injured liver and differentiate into macrophage-like cells that can take up residence there.

To test whether FXR controls this replenishment program, the team used a mouse model of two-thirds partial hepatectomy, the standard experimental system for studying liver regeneration. In wild-type mice, the regenerating lobes showed robust activation of both T cells and Kupffer cells, with increased infiltration of these immune populations into the remnant tissue, exactly the kind of coordinated immune response that regeneration theory predicts. The picture in mice lacking FXR was strikingly different. Although these animals started with elevated baseline numbers of both T cells and Kupffer cells in their livers, once surgery removed two-thirds of the organ, their regenerating livers displayed markedly attenuated immune activation and reduced immune cell infiltration compared with normal mice.

The consequence was a measurable delay in regeneration. The researchers traced this defect to failures in both arms of the Kupffer cell replenishment pathway. In FXR-deficient mice, circulating monocytes were less able to migrate into the regenerating liver, starving the organ of fresh macrophage precursors. At the same time, the resident Kupffer cells that remained proliferated poorly, so the local self-renewal route was also compromised. With both supply lines disrupted, the Kupffer cell pool failed to recover its normal size and composition, and the polarization balance between classically activated M1 macrophages and alternatively activated M2 macrophages was altered, further disturbing the cytokine environment that regenerating hepatocytes require.

Mechanistically, the study identified two molecular pathways through which FXR exerts this control. The first operates on monocyte trafficking. FXR, acting as a transcription factor, directly targets the gene encoding CCR2, the chemokine receptor that serves as the homing beacon for inflammatory monocytes. CCR2 allows circulating monocytes to sense chemokines released by injured tissue and migrate along the gradient toward the wound. By promoting CCR2 expression, FXR effectively keeps the recruitment pipeline open during regeneration. When FXR is absent, this beacon dims, monocytes fail to arrive in sufficient numbers, and the liver loses its most important source of replacement macrophages.

The second pathway governs local proliferation. The researchers found that FXR enhances the expansion of resident Kupffer cells through the CSF1/PI3K/Akt signaling cascade. Colony-stimulating factor 1, or CSF1, is the essential survival and growth factor for cells of the mononuclear phagocyte lineage, and signaling through its receptor activates phosphoinositide 3-kinase and the Akt kinase, a canonical pathway that drives cell growth, survival, and division. By potentiating this cascade in Kupffer cells, FXR ensures that the resident population can double and repopulate the regenerating tissue. The two mechanisms work synergistically: one replenishes the pool from the blood, the other from within, and together they restore Kupffer cell homeostasis at the pace that regeneration demands.

The study also offers a possible explanation for a clinical observation that has long frustrated transplant surgeons and hepatologists: regenerative capacity declines with age. In aged mice, the researchers observed impaired monocyte recruitment to the regenerating liver, mirroring the defect seen in FXR-deficient animals. If the same age-related erosion of the FXR-monocyte axis occurs in humans, it could help explain why elderly patients recover more slowly from major hepatic resection and why organs from older donors regenerate less vigorously after transplantation. This finding reframes aging of the liver not simply as a decline in hepatocyte proliferative potential but as a failure of the immune support system that scaffolds that proliferation.

The clinical implications are considerable. Liver transplantation and partial hepatectomy remain the most effective therapies for end-stage liver disease, yet the persistent shortage of donor organs has intensified interest in interventions that could enhance regeneration, expand the pool of usable grafts, and improve post-surgical outcomes. The identification of the FXR-Kupffer cell axis as a central regulator of liver repair suggests a concrete therapeutic target. Small-molecule FXR agonists, several of which are already approved or in late-stage clinical trials for other liver conditions, could in principle be repurposed or optimized to boost monocyte recruitment and Kupffer cell expansion in patients undergoing hepatic resection or receiving partial grafts from living donors.

As with any mouse study, important questions remain before these findings can be translated. The work was conducted in genetically engineered mice lacking FXR entirely, and the timing, dose, and cell-type specificity of any future pharmacological intervention will need careful optimization. It will also be essential to determine whether activating FXR in humans produces the same immune cell effects without exacerbating the inflammatory components of chronic liver disease, since macrophage polarization is a double-edged sword in conditions such as fibrosis and cirrhosis. Nevertheless, by connecting a well-characterized metabolic receptor to the cellular logistics of immune replenishment, the study adds a compelling new layer to the biology of liver regeneration. It suggests that the liver’s famous ability to rebuild itself rests not only on the proliferative drive of its hepatocytes but on a receptor-controlled program that recruits, renews, and reactivates the macrophages those hepatocytes depend on, and that keeping this program running may one day mean the difference between a graft that thrives and one that fails.

Subject of Research: FXR regulation of Kupffer cell pool restoration during liver regeneration

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

Article References: Ye, W., Zhao, Y., Wang, F., Wang, Y., Qu, Y., Li, Y., Wang, Y.-D., & Chen, W.-D. (2026). An FXR-dependent cellular program for Kupffer cell pool restoration fuels liver regeneration. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03398-z

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03398-z

Keywords: liver regeneration, FXR, Kupffer cells, monocyte recruitment, CCR2, CSF1, PI3K/Akt signaling, partial hepatectomy, macrophage polarization, liver transplantation, aging, nuclear receptor