{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:44:05Z","timestamp":1782837845448,"version":"3.54.5"},"reference-count":48,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The farnesoid X receptor (FXR) is a key metabolic and homeostatic regulator in the liver. In the present work, we identify a novel role of FXR in antagonizing c-Jun N-terminal kinase (JNK) signaling pathway in liver carcinogenesis by activating superoxide dismutase 3 (SOD3) transcription. Compared with wild-type mouse liver, FXR\u2212\/\u2212 mouse liver showed elevated JNK phosphorylation. JNK1 deletion suppressed the increase of diethylnitrosamine-induced tumor number in FXR\u2212\/\u2212 mice. These results suggest that JNK1 plays a key role in chemical-induced liver carcinogenesis in FXR\u2212\/\u2212 mice. We found that ligand-activated FXR was able to alleviate H2O2 or tetradecanoylphorbol acetate-induced JNK phosphorylation in human hepatoblastoma (HepG2) cells or mouse primary hepatocytes. FXR ligand decreased H2O2-induced reactive oxygen species (ROS) levels in wild-type but not FXR\u2212\/\u2212 mouse hepatocytes. FXR knockdown abolished the inhibition of 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]-Benzoic acid (GW4064) on JNK phosphorylation and ROS production induced by H2O2 in HepG2 cells. The gene expression of SOD3, an antioxidant defense enzyme, was increased by FXR activation in vitro and in vivo. An FXR-responsive element, inverted repeat separated by 1 nucleotide in SOD3 promoter, was identified by a combination of transcriptional reporter assays, EMSAs, and chromatin immunoprecipitation assays, which indicated that SOD3 could be a direct FXR target gene. SOD3 knockdown abolished the inhibition of GW4064 on JNK phosphorylation induced by H2O2 in HepG2 cells. In summary, FXR may regulate SOD3 expression to suppress ROS production, resulting in decreasing JNK activity. These results suggest that FXR, as a novel JNK suppressor, may be an attractive therapeutic target for liver cancer treatment.<\/jats:p>","DOI":"10.1210\/me.2014-1225","type":"journal-article","created":{"date-parts":[[2014,12,12]],"date-time":"2014-12-12T17:27:35Z","timestamp":1418405255000},"page":"322-331","source":"Crossref","is-referenced-by-count":43,"title":["Farnesoid X Receptor Antagonizes JNK Signaling Pathway in Liver Carcinogenesis by Activating SOD3"],"prefix":"10.1210","volume":"29","author":[{"given":"Yan-Dong","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Resource Engineering (Y.-D.W., C.G., X.L.), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Dong","family":"Chen","sequence":"first","affiliation":[{"name":"Pathogenic Organisms and Immunology Lab (W.-D.C., C.L.), School of 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