肝内胆管癌 (ICC) 仍然是癌症治疗中的一个重大挑战，特别是因为它对吉西他滨等现有治疗方法具有耐药性，因此需要新的治疗方法。这项研究利用了吉西他滨耐药细胞系、患者来源的器官型肿瘤球体 (PDOT) 和患者衍生的异种移植物 (PDX) 来评估柴胡皂苷-a (SSA) 对 ICC 细胞增殖、迁移、凋亡的影响及其与吉西他滨的潜在协同相互作用。采用转录组测序、荧光素酶报告基因检测和分子对接等技术来阐明分子机制。SSA 在体外和 PDX 模型中均表现出抗肿瘤作用，表明其在 ICC 治疗中具有巨大的潜力。 SSA 通过减少细胞增殖、增强细胞凋亡、减少迁移和侵袭来显着抑制 ICC 进展。至关重要的是，它通过靶向 p-AKT/BCL6/ABCA1 信号通路增强了吉西他滨的功效。这种调节导致 p-AKT 下调和 BCL6 转录活性抑制，最终减少 ABCA1 表达并增强对吉西他滨的化疗敏感性。此外，ABCA1被验证为耐药性的预测生物标志物，ABCA1表达水平与ICC基因谱中各种小分子药物的IC50值之间存在直接相关性。这项研究强调了SSA与吉西他滨联合在增强治疗效果方面的协同潜力反对 ICC 并将 ABCA1 确定为药物反应性的关键生物标志物。此外，新型 PDOT 微流体模型的引入增强了对 ICC 研究的见解。这种组合策略可能会提供一种克服 ICC 治疗挑战的新方法。版权所有 © 2024 作者。由 Elsevier GmbH 出版。保留所有权利。

Intrahepatic cholangiocarcinoma (ICC) remains a significant challenge in cancer therapy, especially due to its resistance to established treatments like Gemcitabine, necessitating novel therapeutic approaches.This study utilized Gemcitabine-resistant cell lines, patient-derived organotypic tumor spheroids (PDOTs), and patient-derived xenografts (PDX) to evaluate the effects of Saikosaponin-a (SSA) on ICC cellular proliferation, migration, apoptosis, and its potential synergistic interaction with Gemcitabine. Techniques such as transcriptome sequencing, Luciferase reporter assays, and molecular docking were employed to unravel the molecular mechanisms.SSA exhibited antitumor effects in both in vitro and PDX models, indicating its considerable potential for ICC treatment. SSA markedly inhibited ICC progression by reducing cellular proliferation, enhancing apoptosis, and decreasing migration and invasion. Crucially, it augmented Gemcitabine's efficacy by targeting the p-AKT/BCL6/ABCA1 signaling pathway. This modulation led to the downregulation of p-AKT and suppression of BCL6 transcriptional activity, ultimately reducing ABCA1 expression and enhancing chemosensitivity to Gemcitabine. Additionally, ABCA1 was validated as a predictive biomarker for drug resistance, with a direct correlation between ABCA1 expression levels and the IC50 values of various small molecule drugs in ICC gene profiles.This study highlights the synergistic potential of SSA combined with Gemcitabine in enhancing therapeutic efficacy against ICC and identifies ABCA1 as a key biomarker for drug responsiveness. Furthermore, the introduction of the novel PDOTs microfluidic model provides enhanced insights into ICC research. This combination strategy may provide a novel approach to overcoming treatment challenges in ICC.Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.