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Background: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y‐box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. Methods: Three bulk and single‐cell RNA‐seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/β‐catenin pathways. Results: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy‐non‐responsive ICC tissues. The YBX1‐high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness‐related pathways. Moreover, YBX1 expression is significantly correlated with several stemness‐related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony‐ and spheroid‐forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/β‐catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/β‐catenin axis. Conclusions: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/β‐catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis. [ABSTRACT FROM AUTHOR]

Currently, the only available curative treatment for intrahepatic cholangiocarcinoma (ICC) is surgical resection, but the survival outcomes are still disappointing. This study aimed to present the surgical outcomes of a large series of ICC patients and investigate the prognostic factors for recurrence and survival. From January 2003 to December 2013, a series of consecutive patients with ICC who underwent curative-intent resection were enrolled. Historical patient records and follow-up results were collected and analyzed. A total of 1842 patients were included in the study, of which 328 (17.8%) experienced complications after surgery with a mortality of 0.3%. The overall survival rates of the entire cohort at 1, 3, and 5 years were 72.5%, 46.9%, and 37.3%, respectively, while the disease-free survival rates at 1, 3, and 5 years were 55.8%, 39.0%, and 23.7%, respectively. Elevated alpha-fetoprotein level, elevated carbohydrate antigen 19–9 level, tumor size > 10 cm, lymphadenectomy, positive lymph node, macrovascular invasion, microvascular invasion, and adjuvant transarterial chemoembolization after surgery were independent predictors for recurrence, while hepatolithiasis, viral hepatitis, elevated carbohydrate antigen 19–9 level, tumor size > 10 cm, lymphadenectomy, positive lymph node, and macrovascular and microvascular invasion were independent prognostic factors for overall survival. Liver resection is safe to treat ICC even when combined with lymphadenectomy. Adequate regional lymphadenectomy should be recommended for all resectable ICC patients to obtain final pathological examination which is essential for predicting recurrence and survival. [ABSTRACT FROM AUTHOR]