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Preprint WatchModerateSeptember 1st, 2026

Hepatic stellate cell FXR signaling regulates context-dependent functions in liver homeostasis and fibrosis.

Vinod, M.; Zummo, F.-P.; Gheeraert, C.; Gouda, Z.; Courquet, S.; Dorchies, E.; Thuret, L.; Lapage, M.; Guille, L.; Bobowski-Gerard, M.; Pourpe, C.; Launay, V.; Derhoudi, M.; Bonnefond, A.; Eberle, D.; Haas, J.; Dubois-Chevalier, J.; Eeckhoute, J.; Lestavel, S.; Staels, B.; Lefebvre, P.; Berthier, A.

Stellate cell FXR is sufficient for the anti-fibrotic effect of the selective FXR agonist tropifexor in precision-cut liver slices, positioning non-hepatocyte FXR as the therapeutic node in fibrotic liver disease.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint extends FXR agonism as a therapeutic axis in fibrotic liver disease by locating the anti-fibrotic effect in hepatic stellate cells rather than hepatocytes, and by showing that tropifexor also drives a proliferative, partial-hepatectomy-like transcriptional program. The Claidex graph holds two FXR failures and neither was an efficacy failure. Both were safety failures. Intercept stopped its pediatric biliary atresia study after an FDA action (obeticholic-acid-nr1h4-fxr-biliary-atresia-phase2-3-safety-hold), and the obeticholic acid plus bezafibrate combination in primary biliary cholangitis was withdrawn on safety grounds (obeticholic-acid-bezafibrate-nr1h4-pbc-phase3-safety-withdrawal). The mechanistic case for FXR has never been the problem in this target's clinical record. The therapeutic index has. A cell-type-restricted agonism strategy is a reasonable response to that history, but any program building on this work should state upfront how stellate-selective engagement would avoid the hepatobiliary and lipid toxicities that closed both prior programs, and how the proliferative transcriptional signature reported here would be monitored in a cirrhotic population.

Abstract excerpt

Nuclear bile acid (BA) signaling plays a central role in liver homeostasis and represents a major therapeutic axis in fibrotic liver diseases. The farnesoid X receptor (FXR), a master nuclear effector of BA signaling, is expressed in several liver-resident cell types, suggesting that it may regulate distinct biological programs beyond the hepatocyte (HC) compartment. Using complementary pharmacological, genetic, and computational approaches across in vitro, ex vivo, and in vivo models of mouse and human origin, we investigated the role of hepatic stellate cell (HSC) FXR (FXRHSC) in both unchallenged and injured livers, which has remained controversial. FXR is robustly expressed in both HCs and HSCs with distinct isoform distributions, and these isoforms exhibited differential capacities to activate gene expression in an HSC context. We found that the potent selective FXR agonist tropifexor triggers a transcriptional program reminiscent of that observed after partial hepatectomy and associated with HC proliferation. This cell cycle-related response was also observed in HSCs and did not require intestinal FXR expression. An HSC-specific response to tropifexor was observed for several genes, including members of the glutathione-S-transferase (GST) family or Scube1. FXRHSC was sufficient to observe the anti-fibrotic effects of tropifexor in precision-cut liver slices, an ex-vivo model of fibrosis. Finally, we identified the regulation of the chemerin-encoding gene Rarres2 as a relevant example of FXRHSC-dependent control of hepatic intercellular communication. Together, these findings identify FXRHSC as an important contributor to hepatic adaptation and therapeutic response to BA analogs and confirmed HSCs as a significant site of nuclear bile acid signaling in liver biology.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.