白血球生成素抑制因子（LIF）是一种细胞因子，属于IL-6家族，其过度表达与癌症患者的不良预后有关，包括胰管腺癌（PDAC）。 LIF信号的传递通过其与异二聚体LIF受体（LIFR）复合物的结合介导，该复合物由LIFR受体和Gp130组成，导致JAK1 / STAT3激活。胆汁酸是影响膜和核受体表达/活性的类固醇，包括法尼索因-X-受体（FXR）和G蛋白胆汁酸活化受体（GPBAR1）。在此，我们调查了FXR和GPBAR1配体是否调节PDAC细胞中LIF / LIFR通路以及这些受体是否在人类肿瘤组织中表达。 PDCA患者队列的转录组分析显示，与对称的非肿瘤组织相比，LIF和LIFR的表达在肿瘤组织中增加。通过体外试验，我们发现一级和二级胆汁酸对LIF / LIFR信号传递具有微弱的拮抗作用。相反，BAR502是一种非胆汁酸类脚环双重FXR和GPBAR1配体，有效抑制LIF与LIFR的结合，其IC50为3.8微米。BAR502以FXR和GPBAR1独立的方式逆转了LIF诱导的模式，表明BAR502在治疗LIFR过度表达的PDAC中可能具有潜在作用。版权所有©2023 Di Giorgio，Bellini，Lupia，Massa，Bordoni，Marchianò，Rosselli，Sepe，Rapacciuolo，Moraca，Morretta，Ricci，Urbani，Monti，Biagioli，Distrutti，Catalanotti，Zampella和Fiorucci。

The leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).Herein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues.The transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM.BAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.Copyright © 2023 Di Giorgio, Bellini, Lupia, Massa, Bordoni, Marchianò, Rosselli, Sepe, Rapacciuolo, Moraca, Morretta, Ricci, Urbani, Monti, Biagioli, Distrutti, Catalanotti, Zampella and Fiorucci.