胰腺导管腺癌（PDAC）恶性程度高，预后差，常见基因突变尚无有效治疗靶点。吉西他滨是 PDAC 的一线化疗药物，由于耐药性，其 5 年生存率低于 10%。 Y 盒结合蛋白 1 (YBX1) 与多药耐药基因激活相关，但在 PDAC 吉西他滨耐药性中仍未阐明。在体内和体外，我们验证了YBX1在胰腺癌细胞中的促进作用，特别是吉西他滨耐药性。 YBX1 通过与 LRP1 启动子区域结合诱导 LRP1 转录，显着改变胰腺癌细胞中 β-catenin 的浓度和分布。通过 TCF3，β-连环蛋白与吉西他滨耐药的关键基因 RRM1 的启动子区域结合，促进 RRM1 表达。在体内和体外实验中，YBX1抑制剂SU056和吉西他滨的联合治疗有效降低了吉西他滨耐药性。 YBX1 高表达通过 YBX1-LRP1-β-catenin-RRM1 轴促进胰腺癌的发病机制和吉西他滨耐药性。将 YBX1 抑制剂与吉西他滨联合使用可能为联合化疗克服吉西他滨耐药性提供新方向，吉西他滨耐药性在胰腺癌化疗期间经常发生。版权所有 © 2024。由 Elsevier B.V. 出版。

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and has a poor prognosis, without effective therapeutic targets in common gene mutations. Gemcitabine, a first-line chemotherapeutic for PDAC, confers <10% 5-year survival rate because of drug resistance. Y-box binding protein 1 (YBX1), associated with multidrug-resistance gene activation, remains unelucidated in PDAC gemcitabine resistance. In vivo and in vitro, we verified YBX1's promotional effects, especially gemcitabine resistance, in pancreatic cancer cells. YBX1-induced LRP1 transcription by binding to the LRP1 promoter region significantly altered the concentration and distribution of β-catenin in pancreatic cancer cells. Through TCF3, β-catenin bound to the promoter region of RRM1, a key gene for gemcitabine resistance, that promotes RRM1 expression. Combination therapy with the YBX1 inhibitor SU056 and gemcitabine effectively reduced gemcitabine resistance in in vivo and in vitro experiments. High YBX1 expression promoted pathogenesis and gemcitabine resistance in pancreatic cancer through the YBX1-LRP1-β-catenin-RRM1 axis. Combining YBX1 inhibitors with gemcitabine may provide a new direction for combination chemotherapy to overcome gemcitabine resistance, which frequently occurs during chemotherapy for pancreatic cancer.Copyright © 2024. Published by Elsevier B.V.