6'-O-乙酰柴胡皂苷D靶向STAT3介导的转录重塑，诱导铁蛋白沉积和细胞凋亡
6''-O-acetylsaikosaponin D targets STAT3-mediated transcriptional remodeling to induce ferroptosis and apoptosis.
摘要(中文译文)
传统药用植物中的天然产物是抗癌药物及药物开发先导化合物的重要来源。柴胡皂苷D（Saikosaponin D，SSD）是一种从柴胡（Radix Bupleuri）中分离得到的五环三萜皂苷，具有抗肿瘤活性，但受限于治疗窗窄和细胞毒性。本研究旨在评估6''-O-乙酰柴胡皂苷D（6''-O-acetylsaikosaponin D，6''-O-acSSD）的抗肿瘤活性并阐明其潜在分子机制。6''-O-acSSD是柴胡中鉴定出的一种天然存在的柴胡皂苷D乙酰化衍生物。研究采用多种癌细胞模型、三维肿瘤球体和患者来源的肿瘤类器官评估了6''-O-acSSD的抗癌效果。通过转录组学和生物信息学分析鉴定受调控的细胞死亡通路。利用分子对接、分子动力学模拟、细胞热位移实验、蛋白质免疫印迹和CUT&Tag图谱分析确定分子靶点并明确转录重编程。6''-O-acSSD显著抑制了癌细胞的增殖、迁移和侵袭，并诱导了与SSD不同的转录程序。转录组学和生化分析揭示其优先激活铁死亡相关特征，包括增强的脂质过氧化。在机制上，6''-O-acSSD靶向STAT3，抑制其磷酸化，并广泛重塑STAT3的染色质占据。功能分析表明，STAT3抑制是6''-O-acSSD发挥完整抗肿瘤活性所必需的。值得注意的是，阻断铁死亡仅能部分恢复细胞活力，而靶向STAT3还额外触发了凋亡相关的转录和生化变化。6''-O-acSSD的抗肿瘤效果在患者来源的肿瘤类器官中得到了进一步验证。6''-O-acSSD通过靶向STAT3依赖性转录程序并诱导铁死亡和凋亡的协同作用，发挥强效抗肿瘤效果。这些发现凸显了结构优化天然产物在抗癌治疗中的治疗潜力。
Abstract
Natural products from traditional medicinal plants represent an important source of anti-cancer agents and lead compounds for drug development. Saikosaponin D (SSD), a triterpenoid saponin isolated from Radix Bupleuri, exhibits anti-tumor activity but is limited by a narrow therapeutic window and cytotoxicity. This study aimed to evaluate the anti-tumor activity of 6''-O-acetylsaikosaponin D (6''-O-acSSD), a naturally occurring acetylated derivative of Saikosaponin D that is identified in Radix Bupleuri, and to elucidate its underlying molecular mechanisms. The anti-cancer effects of 6''-O-acSSD were assessed using multiple cancer cell models, three-dimensional tumor spheroids, and patient-derived tumor organoids. Transcriptomic and bioinformatic analyses were performed to identify regulated cell death pathways. Molecular docking, molecular dynamics simulation, cellular thermal shift assays, western blotting, and CUT&Tag profiling were used to identify molecular targets and define transcriptional reprogramming. 6''-O-acSSD markedly suppressed cancer cell proliferation, migration, and invasion and elicited a transcriptional program distinct from that induced by SSD. Transcriptomic and biochemical analyses revealed preferential activation of ferroptosis-associated signatures, including enhanced lipid peroxidation. Mechanistically, 6''-O-acSSD engaged STAT3, inhibited its phosphorylation, and extensively remodeled STAT3 chromatin occupancy. Functional analyses showed that STAT3 inhibition was required for the full anti-tumor activity of 6''-O-acSSD. Notably, blockade of ferroptosis only partially rescued cell viability, whereas STAT3 targeting additionally triggered apoptosis-associated transcriptional and biochemical changes. The anti-tumor effects of 6''-O-acSSD were further validated in patient-derived tumor organoids. 6''-O-acSSD exerts potent anti-tumor effects by targeting STAT3-dependent transcriptional programs and inducing coordinated ferroptosis and apoptosis. These findings highlight the therapeutic potential of structurally optimized natural products for anti-cancer treatment.
如何引用
AMA
Xuehui Li, Yunxiao Qiao, Xinyi Xu, Jinyu Zhu, Chuang Xie, Shan Lin, et al. 6''-O-acetylsaikosaponin D targets STAT3-mediated transcriptional remodeling to induce ferroptosis and apoptosis.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158301.
APA
Xuehui Li, Yunxiao Qiao, Xinyi Xu, Jinyu Zhu, Chuang Xie, Shan Lin, et al (2026). 6''-O-acetylsaikosaponin D targets STAT3-mediated transcriptional remodeling to induce ferroptosis and apoptosis.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158301
GB/T 7714
Xuehui Li, Yunxiao Qiao, Xinyi Xu, Jinyu Zhu, Chuang Xie, Shan Lin, et al. 6''-O-acetylsaikosaponin D targets STAT3-mediated transcriptional remodeling to induce ferroptosis and apoptosis.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158301.
在 PubMed增强版 阅读全文
翻译全文 · AI 文献问答 · PDF 原文下载 · 引用导出