ArticleThe Journal of biological chemistry2026
Farnesoid X receptor activates STAT3 to promote fatty acid oxidation and suppress inflammatory macrophage responses in cholestasis.
Article in The Journal of biological chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Inflammatory cholangiopathies, including primary sclerosing cholangitis, involve bile duct injury, macrophage-driven inflammation, and progressive fibrosis. While farnesoid X receptor (FXR) regulates bile acid metabolism and immune responses, its role in macrophage immunometabolic reprogramming during cholestasis remains unclear. Here, we investigated whether FXR regulates liver immunometabolism through STAT3-dependent mechanisms in cholestatic liver disease. Using transcriptomic, oxylipin lipidomic, histological, and metabolomic analyses in a chronic murine model of DDC-induced cholangiopathy, we explored the role of FXR-induced STAT3 signaling in regulating inflammatory and metabolic responses. FXR agonists significantly reduced biochemical and histologic cholestatic liver injury as well as suppression of macrophage infiltration. Liver RNA-seq revealed that cholestatic injury activated inflammatory, TGF-β, and arachidonic acid metabolic pathways and reduced fatty acid oxidation (FAO) programs, while FXR restored pathways linked to FAO. Mechanistically, FXR activation in the liver increased STAT3 phosphorylation, acetylation and mitochondrial translocation, boosted STAT3 binding to promoters of genes involving FAO pathways, and triggered the mRNA expression of FAO genes. Pharmacologic STAT3 activation with colivelin reproduced protective effects of GW4064-mediated FXR activation. Conversely, co-administration of the STAT3 inhibitor C-188-9 partially reversed GW4064-mediated suppression of inflammatory and fibrogenic gene programs and reduced induction of FAO genes. Arachidonic acid injection of mice induced macrophage activation and hepatocyte apoptosis, both of which were attenuated by GW4064. STAT3 siRNA knockdown in hepatocyte and macrophage cell systems also blunted FXR agonist-induced transcriptional responses. These findings identify a novel FXR agonist-driven STAT3 immunometabolic axis that integrates bile acid signaling, FAO, and macrophage reprogramming to regulate inflammation during cholestatic liver injury.
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