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Farnesoid X Receptor (FXR) is a bile acid nuclear receptor that was recently found to be upregulated in NSCLC tissues. However, whether and how FXR regulates NSCLC metastasis remains unclear. In the present study, it was found that FXR promoted the migration, invasion, and angiogenic ability of NSCLC cells in vitro, and increased NSCLC metastasis in a mouse model in vivo. Mechanistic investigation demonstrated that FXR specifically bound to the promoters of <jats:italic>IL-6ST<\/jats:italic> and <jats:italic>IL-6<\/jats:italic> genes to upregulate their transcription, thereby leading to activation of the Jak2\/STAT3 signaling pathway, which facilitated tumor migration, invasion, and angiogenesis in NSCLC. Notably, Z-guggulsterone, a natural FXR inhibitor, significantly reduced FXR<jats:sup>high<\/jats:sup> NSCLC metastasis, and decreased the expression of FXR, IL-6, IL-6ST, and p-STAT3 in the mouse model. Clinical analysis verified that FXR was positively correlated with IL-6, IL-6ST and p-STAT3 expression in NSCLC patients, and was indicative of a poor prognosis. 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The animal research was approved by the Institutional Animal Care and Use Committee in Shandong Provincial Hospital. Written informed consent was obtained from all participants. This study was performed in accordance with the Declaration of Helsinki and the guidelines approved by the Ethics Committee in our institution.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors agree to the publication in the journal.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"148"}}