Mi, Wunan and Cigliano, Antonio and Galleri, Grazia and Gigante, Isabella and Steinmann, Sara Martina and Cibali, Ezgi and Serra, Marina and Pes, Giovanni Mario and Schloesser, Denise and Pizzuto, Elena and Siegmund, Heiko I. and Fischer, Claudia and Saborowski, Anna and Giannelli, Gianluigi and Evert, Matthias and Laan, Luc Johannes Wilhelmus van der and Verstegen, Monique Maria Andrea and Calvisi, Diego Francesco (2025) Targeting EIF4A1 is effective against human intrahepatic cholangiocarcinoma. JHEP REPORTS, 7 (7): 101416. ISSN , 2589-5559
Full text not available from this repository. (Request a copy)Abstract
Background & aims: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent primary liver tumor, characterized by clinical aggressiveness, dismal outcome, and limited therapeutic options. Thus, innovative treatments are urgently required to improve the prognosis of patients with iCCA. Methods: In this study, we determined the pathogenetic and therapeutic role of eukaryotic initiation factor 4A1 (EIF4A1), a subunit of the eIF4F complex involved in translation initiation, in human iCCA. Results: Preinvasive (n = 12), invasive (n = 162), and metastatic (n = 14) iCCA lesions exhibited ubiquitous eIF4A1 upregulation. In addition, eIF4A1 mRNA levels from 42 specimens showed a significantly higher expression in iCCA samples compared with non-tumorous tissues (p <0.0001) or large duct-type lesions (p = 0.020). Furthermore, eIF4A1 expression was inversely associated with patient prognosis (p <0.001). Moreover, zotatifin, an eIF4A1-specific inhibitor in clinical trials, significantly reduced the growth of iCCA cell lines, iCCA cancer-associated fibroblasts (CAFs), and patient-derived tumor organoids. At the metabolic level, zotatifin decreased glycolysis of iCCA cells without affecting mitochondrial respiration. Moreover, the Bcl-xl inhibitors A-1155463 and DT2216 profoundly augmented apoptotic cell death when administered in association with zotatifin. Conclusions: The data highlight eIF4A1 as a potential target for treating iCCA. Combined inhibition of eIF4A1 and Bcl-xl could offer an effective therapeutic strategy against this deadly disease.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSLATION; MULTICENTER; EXPRESSION; INITIATION; PREDICTS; Biliary tumors; Zotatifin; Bcl-xl |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Jul 2026 09:08 |
| Last Modified: | 28 Jul 2026 09:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67286 |
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