蟾毒它灵通过下调G6PD破坏氧化还原稳态抑制胰腺癌
Gamabufotalin suppresses pancreatic cancer through redox-homeostasis disruption by G6PD downregulation.
摘要(中文译文)
胰腺癌是全球癌症相关死亡的主要原因之一，凸显了对新型治疗策略的迫切需求。华蟾毒精（Gamabufotalin，CS-6）是一种蟾蜍二烯内酯类化合物，已被证明对多种癌症具有显著的抑制作用。本研究探讨CS-6在胰腺癌中的潜在治疗作用及其分子机制。通过体内和体外实验评估了CS-6的抗癌特性。采用网络药理学和非靶向代谢组学鉴定CS-6的候选分子靶点。利用分子对接、分子动力学模拟和细胞热位移分析（CETSA）支持CS-6与G6PD之间的潜在靶点结合。通过公共数据库和免疫组织化学评估G6PD表达。使用NADPH检测、蛋白质印迹、流式细胞术和透射电子显微镜测定NADPH水平、ROS蓄积、凋亡和自噬。通过转录组分析和蛋白质印迹探讨G6PD下调影响的下游信号通路。CS-6抑制胰腺癌细胞生长、迁移和侵袭，同时促进凋亡。在体内，CS-6抑制肿瘤生长并诱导细胞死亡。胰腺癌中G6PD表达升高与不良预后相关。CS-6处理降低NADPH水平，增加ROS蓄积，并与自噬诱导相关，同时伴有G6PD蛋白表达下降。此外，CS-6抑制PI3K/AKT信号通路，而G6PD敲低可重现该效应。CS-6处理与G6PD下调、氧化还原稳态破坏及PI3K/AKT信号通路抑制相关，从而促进自噬相关细胞死亡、凋亡并抑制胰腺癌进展。这些发现表明CS-6是胰腺癌治疗的有前景的候选药物，而G6PD是潜在的分子靶点。
Abstract
Pancreatic cancer is a leading cause of cancer-related deaths worldwide, highlighting the critical need for novel therapeutic strategies. Gamabufotalin (CS-6), a bufadienolide compound, has been shown to exert significant inhibitory effects on a variety of cancers. This study investigates the potential therapeutic effects and underlying molecular mechanisms of CS-6 in pancreatic cancer. The anti-cancer properties of CS-6 were assessed through both in vivo and in vitro experiments. Network pharmacology and untargeted metabolomics were employed to identify candidate molecular targets of CS-6. Molecular docking, molecular dynamics simulations, and CETSA were used to support potential target engagement between CS-6 and G6PD. G6PD expression was evaluated through public databases and immunohistochemistry. NADPH levels, ROS accumulation, apoptosis, and autophagy were measured using NADPH assays, western blot, flow cytometry, and transmission electron microscopy. Transcriptomic analysis and western blot were conducted to explore the downstream signaling pathways affected by G6PD downregulation. CS-6 inhibited pancreatic cancer cell growth, migration, and invasion, while promoting apoptosis. In vivo, CS-6 suppressed tumor growth and induced cell death. Elevated G6PD expression in pancreatic cancer was associated with poor prognosis. CS-6 treatment reduced NADPH levels, increased ROS accumulation, and was associated with autophagy induction, accompanied by decreased G6PD protein expression. Furthermore, CS-6 inhibited the PI3K/AKT signaling pathway, and G6PD knockdown recapitulated this effect. CS-6 treatment is associated with G6PD downregulation, redox-homeostasis disruption, and suppression of the PI3K/AKT signaling pathway, thereby contributing to autophagy-related cell death, apoptosis, and inhibition of pancreatic cancer progression. These findings highlight CS-6 as a promising therapeutic candidate for pancreatic cancer treatment, with G6PD as a potential molecular target.
如何引用
AMA
Die Xu, Xiaowei Wang, Yisi Cai, Piao Zheng, Lemei Zhu, Weijun Peng, et al. Gamabufotalin suppresses pancreatic cancer through redox-homeostasis disruption by G6PD downregulation.. Journal of translational medicine. 2026; doi:10.1186/s12967-026-08441-2.
APA
Die Xu, Xiaowei Wang, Yisi Cai, Piao Zheng, Lemei Zhu, Weijun Peng, et al (2026). Gamabufotalin suppresses pancreatic cancer through redox-homeostasis disruption by G6PD downregulation.. Journal of translational medicine. https://doi.org/10.1186/s12967-026-08441-2
GB/T 7714
Die Xu, Xiaowei Wang, Yisi Cai, Piao Zheng, Lemei Zhu, Weijun Peng, et al. Gamabufotalin suppresses pancreatic cancer through redox-homeostasis disruption by G6PD downregulation.[J]. Journal of translational medicine, 2026 doi:10.1186/s12967-026-08441-2.
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