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.
Impact and implications: Dysregulation of the translational machinery is a hallmark of cancer, often linked to tumor progression and poor prognosis. This study underscores the potential of zotatifin, a specific inhibitor of EIF4A1 (an essential component of translation initiation) to inhibit the growth of iCCA cells. In addition, zotatifin demonstrated a synergistic effect when used in combination with the Bcl-xl inhibitors A-1155463 and DT2216, significantly enhancing cell apoptosis. Although this investigation did not include an in vivo model, its results, derived from iCCA cell lines, patient-derived organoids, and CAFs, are consistent with the encouraging preliminary results of zotatifin in clinical trials. From a clinical standpoint, these results suggest that zotatifin improves patient outcomes by inhibiting iCCA growth and reducing tumor aggressiveness. Furthermore, combining zotatifin with other drugs could represent a promising therapeutic strategy for targeting iCCA.
Keywords: Bcl-xl; Biliary tumors; EIF4A1; Zotatifin.
© 2025 The Author(s).